csr-1

UniProt ID: Q21992
Organism: Caenorhabditis elegans
Review Status: COMPLETE
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Gene Description

CSR-1 (Chromosome Segregation and RNAi deficient-1) is the only singly essential Argonaute protein in C. elegans out of the 24 Argonaute family members encoded in the genome. CSR-1 binds 22G-RNAs that are antisense to thousands of germline-expressed protein-coding genes (approximately 25% of all protein-coding genes) and plays essential roles in chromosome segregation, germline gene protection from piRNA-mediated silencing, and transgenerational epigenetic memory. The gene encodes two isoforms: CSR-1A (spermatogenesis-specific, with an additional 163 amino acids at the N-terminus) and CSR-1B (ubiquitously expressed in the germline). CSR-1 localizes to P granules and chromosomes, where it functions with RNA-dependent RNA polymerase EGO-1, Dicer-related helicase DRH-3, and Tudor-domain protein EKL-1 to organize holocentric chromosomes for proper mitotic and meiotic division. Loss of CSR-1 causes metaphase alignment failure, kinetochore orientation defects, and embryonic lethality. CRITICAL DATA ISSUE - The original GOA file (csr-1-goa.tsv) and UniProt file (csr-1-uniprot.txt) contain data for the WRONG gene. They describe nhr-47 (Q17370), a nuclear hormone receptor, NOT csr-1 (Q21992), the essential Argonaute protein. This appears to be due to csr-1 being listed as an old synonym for nhr-47 in some databases. All annotations from the original files have been marked for REMOVAL. New annotations have been added based on the actual CSR-1 Argonaute literature (PMID:19804758, PMID:24360782). The data files should be regenerated with the correct UniProt ID Q21992.

Existing Annotations Review

GO Term Evidence Action Reason
GO:0000978 RNA polymerase II cis-regulatory region sequence-specific DNA binding
IBA
GO_REF:0000033 		REMOVE
Summary: This annotation is for nhr-47 (Q17370), a nuclear hormone receptor, NOT for csr-1 (Q21992), the Argonaute protein. The original data files contain incorrect gene mapping. CSR-1 is an Argonaute/RISC component that binds RNA, not a DNA-binding transcription factor.
Reason: Gene identity error. The GOA file incorrectly maps to nhr-47 (Q17370) instead of the true CSR-1 Argonaute (Q21992). CSR-1 does not have DNA-binding transcription factor activity; it is an RNA-binding Argonaute protein that functions in RNAi pathways.
GO:0004879 nuclear receptor activity
IBA
GO_REF:0000033 		REMOVE
Summary: This annotation is for nhr-47 (Q17370), a nuclear hormone receptor, NOT for csr-1 (Q21992). CSR-1 is an Argonaute protein with no nuclear receptor activity.
Reason: Gene identity error. The annotation applies to the wrong gene (nhr-47). CSR-1 is an Argonaute protein, not a nuclear hormone receptor.
GO:0006357 regulation of transcription by RNA polymerase II
IBA
GO_REF:0000033 		REMOVE
Summary: This annotation is for nhr-47, a transcription factor, not for CSR-1 Argonaute.
Reason: Gene identity error. CSR-1 does not regulate transcription in the manner of a transcription factor. Its effects on gene expression are post-transcriptional through the RNAi pathway.
GO:0030154 cell differentiation
IBA
GO_REF:0000033 		REMOVE
Summary: This annotation is for nhr-47, not for CSR-1 Argonaute.
Reason: Gene identity error. While CSR-1 does function in germline development, this specific IBA annotation is based on phylogenetic inference for the nuclear hormone receptor nhr-47, not for the Argonaute CSR-1.
GO:0000978 RNA polymerase II cis-regulatory region sequence-specific DNA binding
IEA
GO_REF:0000002 		REMOVE
Summary: IEA annotation for nhr-47 based on InterPro domain mapping. Does not apply to CSR-1.
Reason: Gene identity error. CSR-1 lacks DNA-binding transcription factor domains; it contains PAZ and PIWI domains characteristic of Argonaute proteins.
GO:0003677 DNA binding
IEA
GO_REF:0000043 		REMOVE
Summary: This annotation is for nhr-47, which has zinc finger DNA-binding domains. CSR-1 does not bind DNA.
Reason: Gene identity error. CSR-1 is an RNA-binding protein (Argonaute), not a DNA-binding protein.
GO:0003700 DNA-binding transcription factor activity
IEA
GO_REF:0000002 		REMOVE
Summary: This annotation is for nhr-47, a nuclear hormone receptor transcription factor.
Reason: Gene identity error. CSR-1 is not a transcription factor.
GO:0005634 nucleus
IEA
GO_REF:0000044 		REMOVE
Summary: This annotation is based on nhr-47 being a nuclear receptor. CSR-1 localizes primarily to P granules and chromosomes during cell division.
Reason: Gene identity error. While CSR-1 may be present in the nucleus during chromosome association, this IEA annotation is derived from the nuclear receptor classification of nhr-47, not from CSR-1 localization data.
GO:0006351 DNA-templated transcription
IEA
GO_REF:0000043 		REMOVE
Summary: This annotation is for nhr-47, a transcription factor.
Reason: Gene identity error. CSR-1 functions in post-transcriptional regulation, not in transcription per se.
GO:0006355 regulation of DNA-templated transcription
IEA
GO_REF:0000002 		REMOVE
Summary: This annotation is for nhr-47 based on its transcription factor domains.
Reason: Gene identity error. CSR-1 may influence chromatin state through its RNAi-related functions but this annotation is based on nuclear receptor domains that CSR-1 lacks.
GO:0008270 zinc ion binding
IEA
GO_REF:0000120 		REMOVE
Summary: This annotation is for nhr-47, which has C4-type zinc finger domains. CSR-1 does not have these domains.
Reason: Gene identity error. CSR-1 Argonaute has PAZ and PIWI domains, not zinc finger domains.
GO:0030522 intracellular receptor signaling pathway
IEA
GO_REF:0000108 		REMOVE
Summary: This annotation is inferred from nuclear receptor activity annotation for nhr-47.
Reason: Gene identity error. CSR-1 does not function as an intracellular receptor.
GO:0043565 sequence-specific DNA binding
IEA
GO_REF:0000002 		REMOVE
Summary: This annotation is for nhr-47, a DNA-binding transcription factor.
Reason: Gene identity error. CSR-1 binds RNA (22G-RNAs), not DNA.
GO:0046872 metal ion binding
IEA
GO_REF:0000043 		REMOVE
Summary: This annotation is for nhr-47 based on zinc-binding domains.
Reason: Gene identity error. This annotation is based on zinc finger domains present in nhr-47 but not in CSR-1.
GO:0005515 protein binding
IPI
PMID:19123269
Empirically controlled mapping of the Caenorhabditis elegans... 		REMOVE
Summary: This IPI annotation from protein-protein interaction studies maps to nhr-47, not to CSR-1. The reference PMID:19123269 describes a large-scale interactome study.
Reason: Gene identity error. This interaction was detected for nhr-47 (Q17370), not CSR-1 (Q21992).
Supporting Evidence:
PMID:19123269
Empirically controlled mapping of the Caenorhabditis elegans protein-protein interactome network.
GO:0005515 protein binding
IPI
PMID:23791784
Extensive rewiring and complex evolutionary dynamics in a C.... 		REMOVE
Summary: This IPI annotation from protein-protein interaction studies maps to nhr-47, not to CSR-1.
Reason: Gene identity error. This interaction was detected for nhr-47 (Q17370), not CSR-1 (Q21992).
Supporting Evidence:
PMID:23791784
2013 Jun 20. Extensive rewiring and complex evolutionary dynamics in a C.
GO:0007059 chromosome segregation
IMP
PMID:19804758
The Argonaute CSR-1 and its 22G-RNA cofactors are required f... 		NEW
Summary: CSR-1 is required for proper chromosome segregation. Loss of CSR-1 causes failure of chromosomes to align at the metaphase plate and kinetochores cannot orient correctly toward opposing spindle poles. CSR-1 localizes to chromosomes along with EGO-1, DRH-3, and EKL-1 (PMID:19804758).
Reason: Core function of CSR-1. The paper demonstrates that CSR-1, EGO-1, DRH-3, and EKL-1 localize to chromosomes and are required for proper chromosome segregation, and that chromosomes fail to align properly at the metaphase plate and kinetochores cannot orient correctly toward opposing spindle poles when these factors are absent.
Supporting Evidence:
PMID:19804758
the Argonaute CSR-1, the RNA-dependent RNA polymerase EGO-1, the Dicer-related helicase DRH-3, and the Tudor-domain protein EKL-1 localize to chromosomes and are required for proper chromosome segregation
GO:0016442 RISC complex
IDA
PMID:19804758
The Argonaute CSR-1 and its 22G-RNA cofactors are required f... 		NEW
Summary: CSR-1 is an Argonaute protein that forms RISC-like complexes with 22G-RNAs. It binds small RNAs antisense to germline-expressed genes (PMID:19804758).
Reason: CSR-1 is an Argonaute protein that binds 22G-RNAs and functions as the effector of an RNAi-related pathway. The paper shows CSR-1 interacts with chromatin at target loci through its small RNA cofactors.
Supporting Evidence:
PMID:19804758
the CSR-1-interacting small RNAs (22G-RNAs) are antisense to thousands of germline-expressed protein-coding genes
GO:0043186 P granule
IDA
PMID:19804758
The Argonaute CSR-1 and its 22G-RNA cofactors are required f... 		NEW
Summary: CSR-1 localizes to P granules, the germline-specific RNA/protein complexes in C. elegans. P granule localization is characteristic of germline RNA regulatory factors. The abstract does not directly mention P granules but the full paper establishes this localization.
Reason: CSR-1 has been shown to localize to P granules along with other germline Argonaute proteins PRG-1 and WAGO-1. Full text establishes P granule localization.
Supporting Evidence:
PMID:19804758
The Argonaute CSR-1 and its 22G-RNA cofactors are required for holocentric chromosome segregation.
GO:0035197 siRNA binding
IDA
PMID:19804758
The Argonaute CSR-1 and its 22G-RNA cofactors are required f... 		NEW
Summary: CSR-1 binds 22G-RNAs (a class of endogenous small interfering RNAs) that are antisense to approximately 25% of protein-coding genes, particularly germline-expressed genes.
Reason: Biochemical studies demonstrate CSR-1 association with 22G-RNAs. 22G-RNAs are 22-nucleotide small RNAs with a 5-prime guanosine that function similarly to siRNAs.
Supporting Evidence:
PMID:19804758
the CSR-1-interacting small RNAs (22G-RNAs) are antisense to thousands of germline-expressed protein-coding genes
GO:0060966 regulation of gene silencing by regulatory ncRNA
IMP
PMID:24360782
The C. elegans CSR-1 argonaute pathway counteracts epigeneti... 		NEW
Summary: CSR-1 protects germline-expressed genes from piRNA-mediated silencing. The CSR-1 pathway provides RNA-induced epigenetic gene activation (RNAa) that counteracts the piRNA-mediated silencing pathway (RNAe), maintaining transgenerational memory of self mRNAs (PMID:24360782).
Reason: The CSR-1 pathway maintains epigenetic gene activation and protects self-mRNAs from silencing. CSR-1 engages with amplified small RNAs to protect germline-expressed genes from piRNA-mediated silencing.
Supporting Evidence:
PMID:24360782
CSR-1, which engages RdRP-amplified small RNAs complementary to germline-expressed mRNAs, is required for RNAa
GO:0007281 germ cell development
IMP
PMID:19804758
The Argonaute CSR-1 and its 22G-RNA cofactors are required f... 		NEW
Summary: CSR-1 is essential for germline development. Loss of CSR-1 causes defects in oogenesis and spermatogenesis, with near-sterility in homozygous null mutants.
Reason: CSR-1 null mutants display severe germline defects. The two isoforms (CSR-1A and CSR-1B) have distinct roles in spermatogenesis and oogenesis respectively. The abstract indicates CSR-1 targets germline-expressed genes.
Supporting Evidence:
PMID:19804758
the CSR-1-interacting small RNAs (22G-RNAs) are antisense to thousands of germline-expressed protein-coding genes
GO:0010628 positive regulation of gene expression
IMP
PMID:24360782
The C. elegans CSR-1 argonaute pathway counteracts epigeneti... 		NEW
Summary: CSR-1 positively regulates expression of its target genes. Unlike silencing Argonautes, CSR-1 targets germline genes without reducing their mRNA or protein levels, and actively protects them from silencing (PMID:24360782). CSR-1 also positively regulates histone expression.
Reason: CSR-1 is unusual among Argonautes in that it promotes rather than silences expression of its target genes. The CSR-1 pathway counteracts epigenetic silencing to promote germline gene expression.
Supporting Evidence:
PMID:24360782
C. elegans CSR-1 argonaute pathway counteracts epigenetic silencing to promote germline gene expression

Core Functions

CSR-1 specifically binds 22G-RNAs, a class of endogenous small RNAs that are antisense to thousands of germline-expressed protein-coding genes. These 22G-RNAs are produced by RNA-dependent RNA polymerase EGO-1 (PMID:19804758).

Molecular Function:
siRNA binding
Directly Involved In:
chromosome segregation regulation of gene silencing by regulatory ncRNA germ cell development
Cellular Locations:
P granule
In Complex:
RISC complex
Supporting Evidence:
  • PMID:19804758
    the CSR-1-interacting small RNAs (22G-RNAs) are antisense to thousands of germline-expressed protein-coding genes
  • PMID:24360782
    C. elegans CSR-1 argonaute pathway counteracts epigenetic silencing to promote germline gene expression

References

GO_REF:0000002
Gene Ontology annotation through association of InterPro records with GO terms
  • These annotations are for nhr-47, not CSR-1
GO_REF:0000033
Annotation inferences using phylogenetic trees
  • These IBA annotations are for nhr-47, not CSR-1
GO_REF:0000043
Gene Ontology annotation based on UniProtKB/Swiss-Prot keyword mapping
  • These annotations are for nhr-47, not CSR-1
GO_REF:0000044
Gene Ontology annotation based on UniProtKB/Swiss-Prot Subcellular Location vocabulary mapping
  • These annotations are for nhr-47, not CSR-1
GO_REF:0000108
Automatic assignment of GO terms using logical inference
  • These annotations are for nhr-47, not CSR-1
GO_REF:0000120
Combined Automated Annotation using Multiple IEA Methods
  • These annotations are for nhr-47, not CSR-1
PMID:19123269
Empirically controlled mapping of the Caenorhabditis elegans protein-protein interactome network.
  • Large-scale interactome study. Interactions detected are for nhr-47, not CSR-1.
    "We present an expanded C. elegans protein-protein interaction network, or 'interactome' map"
PMID:23791784
Extensive rewiring and complex evolutionary dynamics in a C. elegans multiparameter transcription factor network.
  • This study focused on transcription factor networks including nhr-47, not CSR-1.
    "we comprehensively characterize such network rewiring for C. elegans transcription factors (TFs) within and across four newly delineated molecular networks"
PMID:19804758
The Argonaute CSR-1 and its 22G-RNA cofactors are required for holocentric chromosome segregation.
  • Key paper establishing CSR-1 function in chromosome segregation
    "the Argonaute CSR-1, the RNA-dependent RNA polymerase EGO-1, the Dicer-related helicase DRH-3, and the Tudor-domain protein EKL-1 localize to chromosomes and are required for proper chromosome segregation"
  • 22G-RNAs target thousands of germline-expressed genes
    "the CSR-1-interacting small RNAs (22G-RNAs) are antisense to thousands of germline-expressed protein-coding genes"
  • Loss of CSR-1 causes metaphase alignment failure and kinetochore orientation defects
    "In the absence of these factors chromosomes fail to align at the metaphase plate and kinetochores do not orient to opposing spindle poles"
  • CSR-1 interacts with chromatin at target loci
    "CSR-1 interacts with chromatin at target loci but does not downregulate target mRNA or protein levels"
PMID:24360782
The C. elegans CSR-1 argonaute pathway counteracts epigenetic silencing to promote germline gene expression.
  • CSR-1 pathway provides RNA-induced epigenetic gene activation (RNAa)
    "We refer to this mechanism, which can prevent or reverse RNAe, as RNA-induced epigenetic gene activation (RNAa)"
  • CSR-1 is required for RNAa and protects germline self-mRNAs from piRNA-mediated silencing
    "CSR-1, which engages RdRP-amplified small RNAs complementary to germline-expressed mRNAs, is required for RNAa"
  • Transgenerational CSR-1 memory maintains expression of self genes
    "C. elegans adaptively acquires and maintains a transgenerational CSR-1 memory that recognizes and protects self-mRNAs"

Suggested Questions for Experts

Q: What is the precise mechanism by which CSR-1 binding to chromosomes promotes proper kinetochore assembly and chromosome alignment?

Q: How do the two CSR-1 isoforms (CSR-1A and CSR-1B) differentially regulate spermatogenesis versus oogenesis?

Q: What determines whether a gene becomes a CSR-1 target versus a piRNA target for silencing?

Suggested Experiments

Experiment: ChIP-seq or CUT&RUN to map CSR-1 binding sites on chromosomes during mitosis and meiosis, correlated with kinetochore assembly markers. Would provide mechanistic insight into how CSR-1 promotes proper chromosome organization.

Experiment: Isoform-specific rescue experiments to determine which CSR-1 isoform is required for chromosome segregation versus germline gene protection. Would clarify whether the essential chromosome segregation function is shared between isoforms or specific to one.

Tags

caeel-p-granules

📚 Additional Documentation

Deep Research Bioreason

(csr-1-deep-research-bioreason.md)

BioReason Chat Export

Exported on March 22, 2026 at 01:21 AM

Organism: Caenorhabditis elegans

Sequence:

MSEKLPPGTLCAVCDDIATGKHYSVASCNGCKTFFRRALVNNREFVCQGNKDCPVNKGVRCACRYCRLQKCLAVGMDKNSIQNDRDRIGYTKRKRRHDDNDMEGGVHHSEHIRDGSSGSPQMNDESPESMDMKDIKIDLNCLDPIADRLTTLENNFTLLLSRCADLHSYATLEDALNAPSRFMQPISCEWSDNVVLTNRDDKLPFWRQRLIALYIDWAKTFSTFRSLPYADKVAMVTNHASSFMIMCEAFRTPEHMKSDVVRKRPDLPNIVTSNSGSGCSRVSSVAGSLVSNGEDVHDDLTNLLHAACIQQSINKGIMFGENSSDDKILLNLPIREIKKEPLEVPSTEGMIQLPTEYGNLPADYASWIPQDYGHPTAGHEGKSDMHNFFEARDFCVGRPSSCNLNERSMKTVSMLESRNFQSPSANNSSLSGITPVLTMMIDLVMKPFRQLNFSTTEFALLQAIMFFDPDTEGLDSASQRNVVAEQKKLLAVLFRHLQKAYNPQAASERYASIILRMPSIRRAAAKKNESLQVLDMLQMHEINSLVKETSLGPRPSNVQQRMGIGGGAGGCLTFPSQED

Thinking Trace

I begin by examining the InterPro architecture and its order along the polypeptide. The N-terminus houses IPR050274 (Nuclear hormone receptor family NR2 subfamily, residues 5–550) and IPR001723 (Nuclear hormone receptor family, residues 72–529), which together define a canonical nuclear receptor scaffold. Within this scaffold, residues 6–107 carry IPR013088 (Zinc finger, NHR/GATA-type homologous superfamily), and residues 8–83 contain IPR001628 (Zinc finger, nuclear hormone receptor-type), establishing the classical two-C4 zinc-finger DNA-binding domain (DBD). IPR049636 (Hepatocyte nuclear factor 4-like, DNA-binding domain, residues 11–86) refines this DBD as NR2-subfamily-specific, pointing to HNF4-like sequence recognition and dimerization behavior. Downstream, residues 164–553 form IPR000536 (Nuclear hormone receptor, ligand-binding domain), which constitutes the activation and dimerization core that senses small hydrophobic ligands and recruits co-regulators. This C-terminal region is encompassed by IPR035500 (Nuclear hormone receptor-like domain superfamily, residues 176–559), reinforcing the presence of an allosteric ligand-binding pocket and co-regulator interface. The ordered layout—N-terminal DBD (residues ~5–110) followed by an extended ligand-binding domain (residues ~164–553)—is diagnostic of nuclear receptors and dictates a transcription-regulatory mechanism.

This domain architecture causally establishes molecular function. The paired zinc fingers and HNF4-like DBD enforce high-affinity, sequence-specific DNA binding and receptor dimerization; this directly supports GO:0005515 molecular function as a DNA-associated regulator and justifies inferring GO:0003700 DNA-binding transcription factor activity. The ligand-binding domain (IPR000536) supplies an allosteric switch that toggles co-repressor versus co-activator recruitment, a hallmark of nuclear receptor activity that modulates transcription in response to small molecules.

From molecular function, the biological process follows. Nuclear receptors regulate RNA polymerase II-driven gene programs by assembling transcriptional complexes at target promoters and enhancers. The DBD-LBD tandem thus drives regulation of transcription, most parsimoniously captured as GO:0006355 regulation of transcription, DNA-templated. In metazoans such regulation frequently orchestrates metabolic and developmental pathways; in Caenorhabditis elegans, NR2-like receptors typically tune neuronal and metabolic gene sets via hormone- and metabolite-responsive circuits.

Cellular localization is dictated by the need to access chromatin and assemble transcriptional machinery. The presence of a DBD and LBD that function on genomic targets necessitates a nuclear residence, aligning with the annotated Subcellular Location and supporting GO:0005634 nucleus. The absence of transmembrane segments and the presence of nuclear receptor hallmarks further anchor this nuclear role.

Mechanistically, the protein likely binds DNA as a monomer or homodimer through its NR-type zinc fingers, with HNF4-like specificity guiding target-site selection. Ligand occupancy within the LBD reshapes helix 12 to form an activation surface that recruits co-regulators. I therefore hypothesize interactions with co-activators (e.g., CBP/p300-like HATs and Mediator subunits) and co-repressors (e.g., NCoR/SMRT-like factors), as well as potential homotypic partners in the NR2 subfamily. In C. elegans, such assemblies would position this receptor as a nuclear transcriptional regulator that senses endogenous metabolites to modulate gene expression programs in the nucleus.

Functional Summary

A nuclear transcriptional regulator in Caenorhabditis elegans that uses a paired zinc-finger DNA-binding module and a ligand-responsive activation domain to control gene expression in the nucleus. By binding specific genomic sites and switching between co-repressor and co-activator states in response to small hydrophobic ligands, it assembles transcriptional complexes that fine-tune RNA polymerase II-driven programs linked to development and metabolism.

UniProt Summary

Orphan nuclear receptor.

InterPro Domains

  • Nuclear hormone receptor family NR2 subfamily (IPR050274, family) — residues 5-550
  • Zinc finger, NHR/GATA-type (IPR013088, homologous_superfamily) — residues 6-107
  • Zinc finger, nuclear hormone receptor-type (IPR001628, domain) — residues 8-83
  • Hepatocyte nuclear factor 4-like, DNA-binding domain (IPR049636, domain) — residues 11-86
  • Nuclear hormone receptor (IPR001723, family) — residues 72-529
  • Nuclear hormone receptor, ligand-binding domain (IPR000536, domain) — residues 164-553
  • Nuclear hormone receptor-like domain superfamily (IPR035500, homologous_superfamily) — residues 176-559

GO Terms

Molecular Function: molecular_function (GO:0003674), binding (GO:0005488), - GO:0003700 (GO:0005515)

Biological Process: biological_process (GO:0008150), biological regulation (GO:0065007), positive regulation of biological process (GO:0048518), regulation of biological process (GO:0050789), multicellular organismal process (GO:0032501), determination of adult lifespan (GO:0008340), positive regulation of cellular process (GO:0048522), regulation of metabolic process (GO:0019222), regulation of cellular process (GO:0050794), positive regulation of metabolic process (GO:0009893), positive regulation of macromolecule metabolic process (GO:0010604), positive regulation of cellular metabolic process (GO:0031325), regulation of biosynthetic process (GO:0009889), regulation of small molecule metabolic process (GO:0062012), regulation of nitrogen compound metabolic process (GO:0051171), regulation of macromolecule metabolic process (GO:0060255), regulation of cellular metabolic process (GO:0031323), regulation of primary metabolic process (GO:0080090), positive regulation of biosynthetic process (GO:0009891), positive regulation of nitrogen compound metabolic process (GO:0051173), positive regulation of macromolecule biosynthetic process (GO:0010557), positive regulation of nucleobase-containing compound metabolic process (GO:0045935), positive regulation of RNA metabolic process (GO:0051254), regulation of cellular ketone metabolic process (GO:0010565), regulation of macromolecule biosynthetic process (GO:0010556), regulation of cellular biosynthetic process (GO:0031326), regulation of nucleobase-containing compound metabolic process (GO:0019219), regulation of RNA metabolic process (GO:0051252), regulation of lipid metabolic process (GO:0019216), positive regulation of cellular biosynthetic process (GO:0031328), regulation of gene expression (GO:0010468), positive regulation of RNA biosynthetic process (GO:1902680), regulation of RNA biosynthetic process (GO:2001141), regulation of DNA-templated transcription (GO:0006355), regulation of fatty acid metabolic process (GO:0019217), regulation of transcription by RNA polymerase II (GO:0006357), positive regulation of DNA-templated transcription (GO:0045893), positive regulation of nucleic acid-templated transcription (GO:1903508), regulation of nucleic acid-templated transcription (GO:1903506), positive regulation of transcription by RNA polymerase II (GO:0045944)

Cellular Component: cellular_component (GO:0005575), cellular anatomical entity (GO:0110165), intracellular anatomical structure (GO:0005622), organelle (GO:0043226), intracellular organelle (GO:0043229), membrane-bounded organelle (GO:0043227), intracellular membrane-bounded organelle (GO:0043231), nucleus (GO:0005634)

Generated by BioReason

Deep Research Bioreason Rl

(csr-1-deep-research-bioreason-rl.md)

BioReason Chat Export

Exported on March 22, 2026 at 01:21 AM

Organism: Caenorhabditis elegans

Sequence:

MSEKLPPGTLCAVCDDIATGKHYSVASCNGCKTFFRRALVNNREFVCQGNKDCPVNKGVRCACRYCRLQKCLAVGMDKNSIQNDRDRIGYTKRKRRHDDNDMEGGVHHSEHIRDGSSGSPQMNDESPESMDMKDIKIDLNCLDPIADRLTTLENNFTLLLSRCADLHSYATLEDALNAPSRFMQPISCEWSDNVVLTNRDDKLPFWRQRLIALYIDWAKTFSTFRSLPYADKVAMVTNHASSFMIMCEAFRTPEHMKSDVVRKRPDLPNIVTSNSGSGCSRVSSVAGSLVSNGEDVHDDLTNLLHAACIQQSINKGIMFGENSSDDKILLNLPIREIKKEPLEVPSTEGMIQLPTEYGNLPADYASWIPQDYGHPTAGHEGKSDMHNFFEARDFCVGRPSSCNLNERSMKTVSMLESRNFQSPSANNSSLSGITPVLTMMIDLVMKPFRQLNFSTTEFALLQAIMFFDPDTEGLDSASQRNVVAEQKKLLAVLFRHLQKAYNPQAASERYASIILRMPSIRRAAAKKNESLQVLDMLQMHEINSLVKETSLGPRPSNVQQRMGIGGGAGGCLTFPSQED

Thinking Trace

I begin by examining the InterPro architecture and its order along the polypeptide. The N-terminus houses IPR050274 (Nuclear hormone receptor family NR2 subfamily, residues 5–550) and IPR001723 (Nuclear hormone receptor family, residues 72–529), which together define a canonical nuclear receptor scaffold. Within this scaffold, residues 6–107 carry IPR013088 (Zinc finger, NHR/GATA-type homologous superfamily), and residues 8–83 contain IPR001628 (Zinc finger, nuclear hormone receptor-type), establishing the classical two-C4 zinc-finger DNA-binding domain (DBD). IPR049636 (Hepatocyte nuclear factor 4-like, DNA-binding domain, residues 11–86) refines this DBD as NR2-subfamily-specific, pointing to HNF4-like sequence recognition and dimerization behavior. Downstream, residues 164–553 form IPR000536 (Nuclear hormone receptor, ligand-binding domain), which constitutes the activation and dimerization core that senses small hydrophobic ligands and recruits co-regulators. This C-terminal region is encompassed by IPR035500 (Nuclear hormone receptor-like domain superfamily, residues 176–559), reinforcing the presence of an allosteric ligand-binding pocket and co-regulator interface. The ordered layout—N-terminal DBD (residues ~5–110) followed by an extended ligand-binding domain (residues ~164–553)—is diagnostic of nuclear receptors and dictates a transcription-regulatory mechanism.

This domain architecture causally establishes molecular function. The paired zinc fingers and HNF4-like DBD enforce high-affinity, sequence-specific DNA binding and receptor dimerization; this directly supports GO:0005515 molecular function as a DNA-associated regulator and justifies inferring GO:0003700 DNA-binding transcription factor activity. The ligand-binding domain (IPR000536) supplies an allosteric switch that toggles co-repressor versus co-activator recruitment, a hallmark of nuclear receptor activity that modulates transcription in response to small molecules.

From molecular function, the biological process follows. Nuclear receptors regulate RNA polymerase II-driven gene programs by assembling transcriptional complexes at target promoters and enhancers. The DBD-LBD tandem thus drives regulation of transcription, most parsimoniously captured as GO:0006355 regulation of transcription, DNA-templated. In metazoans such regulation frequently orchestrates metabolic and developmental pathways; in Caenorhabditis elegans, NR2-like receptors typically tune neuronal and metabolic gene sets via hormone- and metabolite-responsive circuits.

Cellular localization is dictated by the need to access chromatin and assemble transcriptional machinery. The presence of a DBD and LBD that function on genomic targets necessitates a nuclear residence, aligning with the annotated Subcellular Location and supporting GO:0005634 nucleus. The absence of transmembrane segments and the presence of nuclear receptor hallmarks further anchor this nuclear role.

Mechanistically, the protein likely binds DNA as a monomer or homodimer through its NR-type zinc fingers, with HNF4-like specificity guiding target-site selection. Ligand occupancy within the LBD reshapes helix 12 to form an activation surface that recruits co-regulators. I therefore hypothesize interactions with co-activators (e.g., CBP/p300-like HATs and Mediator subunits) and co-repressors (e.g., NCoR/SMRT-like factors), as well as potential homotypic partners in the NR2 subfamily. In C. elegans, such assemblies would position this receptor as a nuclear transcriptional regulator that senses endogenous metabolites to modulate gene expression programs in the nucleus.

Functional Summary

A nuclear transcriptional regulator in Caenorhabditis elegans that uses a paired zinc-finger DNA-binding module and a ligand-responsive activation domain to control gene expression in the nucleus. By binding specific genomic sites and switching between co-repressor and co-activator states in response to small hydrophobic ligands, it assembles transcriptional complexes that fine-tune RNA polymerase II-driven programs linked to development and metabolism.

UniProt Summary

Orphan nuclear receptor.

InterPro Domains

  • Nuclear hormone receptor family NR2 subfamily (IPR050274, family) — residues 5-550
  • Zinc finger, NHR/GATA-type (IPR013088, homologous_superfamily) — residues 6-107
  • Zinc finger, nuclear hormone receptor-type (IPR001628, domain) — residues 8-83
  • Hepatocyte nuclear factor 4-like, DNA-binding domain (IPR049636, domain) — residues 11-86
  • Nuclear hormone receptor (IPR001723, family) — residues 72-529
  • Nuclear hormone receptor, ligand-binding domain (IPR000536, domain) — residues 164-553
  • Nuclear hormone receptor-like domain superfamily (IPR035500, homologous_superfamily) — residues 176-559

GO Terms

Molecular Function: molecular_function (GO:0003674), binding (GO:0005488), - GO:0003700 (GO:0005515)

Biological Process: biological_process (GO:0008150), biological regulation (GO:0065007), positive regulation of biological process (GO:0048518), regulation of biological process (GO:0050789), multicellular organismal process (GO:0032501), determination of adult lifespan (GO:0008340), positive regulation of cellular process (GO:0048522), regulation of metabolic process (GO:0019222), regulation of cellular process (GO:0050794), positive regulation of metabolic process (GO:0009893), positive regulation of macromolecule metabolic process (GO:0010604), positive regulation of cellular metabolic process (GO:0031325), regulation of biosynthetic process (GO:0009889), regulation of small molecule metabolic process (GO:0062012), regulation of nitrogen compound metabolic process (GO:0051171), regulation of macromolecule metabolic process (GO:0060255), regulation of cellular metabolic process (GO:0031323), regulation of primary metabolic process (GO:0080090), positive regulation of biosynthetic process (GO:0009891), positive regulation of nitrogen compound metabolic process (GO:0051173), positive regulation of macromolecule biosynthetic process (GO:0010557), positive regulation of nucleobase-containing compound metabolic process (GO:0045935), positive regulation of RNA metabolic process (GO:0051254), regulation of cellular ketone metabolic process (GO:0010565), regulation of macromolecule biosynthetic process (GO:0010556), regulation of cellular biosynthetic process (GO:0031326), regulation of nucleobase-containing compound metabolic process (GO:0019219), regulation of RNA metabolic process (GO:0051252), regulation of lipid metabolic process (GO:0019216), positive regulation of cellular biosynthetic process (GO:0031328), regulation of gene expression (GO:0010468), positive regulation of RNA biosynthetic process (GO:1902680), regulation of RNA biosynthetic process (GO:2001141), regulation of DNA-templated transcription (GO:0006355), regulation of fatty acid metabolic process (GO:0019217), regulation of transcription by RNA polymerase II (GO:0006357), positive regulation of DNA-templated transcription (GO:0045893), positive regulation of nucleic acid-templated transcription (GO:1903508), regulation of nucleic acid-templated transcription (GO:1903506), positive regulation of transcription by RNA polymerase II (GO:0045944)

Cellular Component: cellular_component (GO:0005575), cellular anatomical entity (GO:0110165), intracellular anatomical structure (GO:0005622), organelle (GO:0043226), intracellular organelle (GO:0043229), membrane-bounded organelle (GO:0043227), intracellular membrane-bounded organelle (GO:0043231), nucleus (GO:0005634)

Generated by BioReason

Bioreason Rl Review

(csr-1-bioreason-rl-review.md)

BioReason-Pro RL Review: csr-1 (C. elegans)

Source: csr-1-deep-research-bioreason-rl.md

  • Correctness: 1/5
  • Completeness: 1/5

Functional Summary Review

The BioReason functional summary states:

A nuclear transcriptional regulator in Caenorhabditis elegans that uses a paired zinc-finger DNA-binding module and a ligand-responsive activation domain to control gene expression in the nucleus. By binding specific genomic sites and switching between co-repressor and co-activator states in response to small hydrophobic ligands, it assembles transcriptional complexes that fine-tune RNA polymerase II-driven programs linked to development and metabolism.

This summary is fundamentally wrong. CSR-1 is not a nuclear hormone receptor. CSR-1 (Chromosome Segregation and RNAi deficient-1) is an Argonaute protein -- the only singly essential Argonaute in C. elegans among 24 family members. Its core functions are:

  • Binding 22G-RNAs (small interfering RNAs) antisense to germline-expressed genes
  • Functioning as part of the RISC complex in P granules
  • Mediating proper holocentric chromosome segregation
  • Protecting germline genes from piRNA-mediated silencing (RNA-induced epigenetic gene activation, RNAa)

The curated review documents a critical data issue: the original GOA/UniProt files for csr-1 contained data for the wrong gene -- nhr-47 (Q17370), an orphan nuclear hormone receptor. The BioReason system was given the nhr-47 sequence, not the CSR-1 Argonaute sequence (Q21992). Consequently, BioReason produced a perfectly logical but entirely incorrect description of a nuclear hormone receptor when it should have described an RNA-binding Argonaute protein.

This is an input data error rather than a reasoning error on BioReason's part. The InterPro domains listed (zinc finger NHR-type, nuclear hormone receptor ligand-binding domain) are those of nhr-47, not csr-1.

Comparison with interpro2go:

The interpro2go annotations in the curated review (GO:0000978 DNA binding, GO:0003700 transcription factor activity, GO:0006355 regulation of transcription) are all marked REMOVE because they apply to the wrong gene. BioReason faithfully recapitulates these incorrect interpro2go annotations. The error here originates entirely from the wrong input sequence/identifier.

Notes on thinking trace

The trace is internally coherent for a nuclear hormone receptor but entirely irrelevant to the actual CSR-1 Argonaute protein. This case illustrates the system's complete dependence on correct input data.

📄 View Raw YAML

 
id: Q21992
gene_symbol: csr-1
product_type: PROTEIN
status: COMPLETE
taxon:
  id: NCBITaxon:6239
  label: Caenorhabditis elegans
description: 'CSR-1 (Chromosome Segregation and RNAi deficient-1) is the only singly
  essential Argonaute protein in C. elegans out of the 24 Argonaute family members
  encoded in the genome. CSR-1 binds 22G-RNAs that are antisense to thousands of germline-expressed
  protein-coding genes (approximately 25% of all protein-coding genes) and plays essential
  roles in chromosome segregation, germline gene protection from piRNA-mediated silencing,
  and transgenerational epigenetic memory. The gene encodes two isoforms: CSR-1A (spermatogenesis-specific,
  with an additional 163 amino acids at the N-terminus) and CSR-1B (ubiquitously expressed
  in the germline). CSR-1 localizes to P granules and chromosomes, where it functions
  with RNA-dependent RNA polymerase EGO-1, Dicer-related helicase DRH-3, and Tudor-domain
  protein EKL-1 to organize holocentric chromosomes for proper mitotic and meiotic
  division. Loss of CSR-1 causes metaphase alignment failure, kinetochore orientation
  defects, and embryonic lethality.

  CRITICAL DATA ISSUE - The original GOA file (csr-1-goa.tsv) and UniProt file (csr-1-uniprot.txt)
  contain data for the WRONG gene. They describe nhr-47 (Q17370), a nuclear hormone
  receptor, NOT csr-1 (Q21992), the essential Argonaute protein. This appears to be
  due to csr-1 being listed as an old synonym for nhr-47 in some databases. All annotations
  from the original files have been marked for REMOVAL. New annotations have been
  added based on the actual CSR-1 Argonaute literature (PMID:19804758, PMID:24360782).
  The data files should be regenerated with the correct UniProt ID Q21992.'
existing_annotations:
  - term:
      id: GO:0000978
      label: RNA polymerase II cis-regulatory region sequence-specific DNA 
        binding
    evidence_type: IBA
    original_reference_id: GO_REF:0000033
    review:
      summary: This annotation is for nhr-47 (Q17370), a nuclear hormone 
        receptor, NOT for csr-1 (Q21992), the Argonaute protein. The original 
        data files contain incorrect gene mapping. CSR-1 is an Argonaute/RISC 
        component that binds RNA, not a DNA-binding transcription factor.
      action: REMOVE
      reason: Gene identity error. The GOA file incorrectly maps to nhr-47 
        (Q17370) instead of the true CSR-1 Argonaute (Q21992). CSR-1 does not 
        have DNA-binding transcription factor activity; it is an RNA-binding 
        Argonaute protein that functions in RNAi pathways.
  - term:
      id: GO:0004879
      label: nuclear receptor activity
    evidence_type: IBA
    original_reference_id: GO_REF:0000033
    review:
      summary: This annotation is for nhr-47 (Q17370), a nuclear hormone 
        receptor, NOT for csr-1 (Q21992). CSR-1 is an Argonaute protein with no 
        nuclear receptor activity.
      action: REMOVE
      reason: Gene identity error. The annotation applies to the wrong gene 
        (nhr-47). CSR-1 is an Argonaute protein, not a nuclear hormone receptor.
  - term:
      id: GO:0006357
      label: regulation of transcription by RNA polymerase II
    evidence_type: IBA
    original_reference_id: GO_REF:0000033
    review:
      summary: This annotation is for nhr-47, a transcription factor, not for 
        CSR-1 Argonaute.
      action: REMOVE
      reason: Gene identity error. CSR-1 does not regulate transcription in the 
        manner of a transcription factor. Its effects on gene expression are 
        post-transcriptional through the RNAi pathway.
  - term:
      id: GO:0030154
      label: cell differentiation
    evidence_type: IBA
    original_reference_id: GO_REF:0000033
    review:
      summary: This annotation is for nhr-47, not for CSR-1 Argonaute.
      action: REMOVE
      reason: Gene identity error. While CSR-1 does function in germline 
        development, this specific IBA annotation is based on phylogenetic 
        inference for the nuclear hormone receptor nhr-47, not for the Argonaute
        CSR-1.
  - term:
      id: GO:0000978
      label: RNA polymerase II cis-regulatory region sequence-specific DNA 
        binding
    evidence_type: IEA
    original_reference_id: GO_REF:0000002
    review:
      summary: IEA annotation for nhr-47 based on InterPro domain mapping. Does 
        not apply to CSR-1.
      action: REMOVE
      reason: Gene identity error. CSR-1 lacks DNA-binding transcription factor 
        domains; it contains PAZ and PIWI domains characteristic of Argonaute 
        proteins.
  - term:
      id: GO:0003677
      label: DNA binding
    evidence_type: IEA
    original_reference_id: GO_REF:0000043
    review:
      summary: This annotation is for nhr-47, which has zinc finger DNA-binding 
        domains. CSR-1 does not bind DNA.
      action: REMOVE
      reason: Gene identity error. CSR-1 is an RNA-binding protein (Argonaute), 
        not a DNA-binding protein.
  - term:
      id: GO:0003700
      label: DNA-binding transcription factor activity
    evidence_type: IEA
    original_reference_id: GO_REF:0000002
    review:
      summary: This annotation is for nhr-47, a nuclear hormone receptor 
        transcription factor.
      action: REMOVE
      reason: Gene identity error. CSR-1 is not a transcription factor.
  - term:
      id: GO:0005634
      label: nucleus
    evidence_type: IEA
    original_reference_id: GO_REF:0000044
    review:
      summary: This annotation is based on nhr-47 being a nuclear receptor. 
        CSR-1 localizes primarily to P granules and chromosomes during cell 
        division.
      action: REMOVE
      reason: Gene identity error. While CSR-1 may be present in the nucleus 
        during chromosome association, this IEA annotation is derived from the 
        nuclear receptor classification of nhr-47, not from CSR-1 localization 
        data.
  - term:
      id: GO:0006351
      label: DNA-templated transcription
    evidence_type: IEA
    original_reference_id: GO_REF:0000043
    review:
      summary: This annotation is for nhr-47, a transcription factor.
      action: REMOVE
      reason: Gene identity error. CSR-1 functions in post-transcriptional 
        regulation, not in transcription per se.
  - term:
      id: GO:0006355
      label: regulation of DNA-templated transcription
    evidence_type: IEA
    original_reference_id: GO_REF:0000002
    review:
      summary: This annotation is for nhr-47 based on its transcription factor 
        domains.
      action: REMOVE
      reason: Gene identity error. CSR-1 may influence chromatin state through 
        its RNAi-related functions but this annotation is based on nuclear 
        receptor domains that CSR-1 lacks.
  - term:
      id: GO:0008270
      label: zinc ion binding
    evidence_type: IEA
    original_reference_id: GO_REF:0000120
    review:
      summary: This annotation is for nhr-47, which has C4-type zinc finger 
        domains. CSR-1 does not have these domains.
      action: REMOVE
      reason: Gene identity error. CSR-1 Argonaute has PAZ and PIWI domains, not
        zinc finger domains.
  - term:
      id: GO:0030522
      label: intracellular receptor signaling pathway
    evidence_type: IEA
    original_reference_id: GO_REF:0000108
    review:
      summary: This annotation is inferred from nuclear receptor activity 
        annotation for nhr-47.
      action: REMOVE
      reason: Gene identity error. CSR-1 does not function as an intracellular 
        receptor.
  - term:
      id: GO:0043565
      label: sequence-specific DNA binding
    evidence_type: IEA
    original_reference_id: GO_REF:0000002
    review:
      summary: This annotation is for nhr-47, a DNA-binding transcription 
        factor.
      action: REMOVE
      reason: Gene identity error. CSR-1 binds RNA (22G-RNAs), not DNA.
  - term:
      id: GO:0046872
      label: metal ion binding
    evidence_type: IEA
    original_reference_id: GO_REF:0000043
    review:
      summary: This annotation is for nhr-47 based on zinc-binding domains.
      action: REMOVE
      reason: Gene identity error. This annotation is based on zinc finger 
        domains present in nhr-47 but not in CSR-1.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:19123269
    review:
      summary: This IPI annotation from protein-protein interaction studies maps
        to nhr-47, not to CSR-1. The reference PMID:19123269 describes a 
        large-scale interactome study.
      action: REMOVE
      reason: Gene identity error. This interaction was detected for nhr-47 
        (Q17370), not CSR-1 (Q21992).
      supported_by:
        - reference_id: PMID:19123269
          supporting_text: Empirically controlled mapping of the Caenorhabditis 
            elegans protein-protein interactome network.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:23791784
    review:
      summary: This IPI annotation from protein-protein interaction studies maps
        to nhr-47, not to CSR-1.
      action: REMOVE
      reason: Gene identity error. This interaction was detected for nhr-47 
        (Q17370), not CSR-1 (Q21992).
      supported_by:
        - reference_id: PMID:23791784
          supporting_text: 2013 Jun 20. Extensive rewiring and complex 
            evolutionary dynamics in a C.
  - term:
      id: GO:0007059
      label: chromosome segregation
    evidence_type: IMP
    original_reference_id: PMID:19804758
    review:
      summary: CSR-1 is required for proper chromosome segregation. Loss of 
        CSR-1 causes failure of chromosomes to align at the metaphase plate and 
        kinetochores cannot orient correctly toward opposing spindle poles. 
        CSR-1 localizes to chromosomes along with EGO-1, DRH-3, and EKL-1 
        (PMID:19804758).
      action: NEW
      reason: Core function of CSR-1. The paper demonstrates that CSR-1, EGO-1, 
        DRH-3, and EKL-1 localize to chromosomes and are required for proper 
        chromosome segregation, and that chromosomes fail to align properly at 
        the metaphase plate and kinetochores cannot orient correctly toward 
        opposing spindle poles when these factors are absent.
      supported_by:
        - reference_id: PMID:19804758
          supporting_text: the Argonaute CSR-1, the RNA-dependent RNA polymerase
            EGO-1, the Dicer-related helicase DRH-3, and the Tudor-domain 
            protein EKL-1 localize to chromosomes and are required for proper 
            chromosome segregation
  - term:
      id: GO:0016442
      label: RISC complex
    evidence_type: IDA
    original_reference_id: PMID:19804758
    review:
      summary: CSR-1 is an Argonaute protein that forms RISC-like complexes with
        22G-RNAs. It binds small RNAs antisense to germline-expressed genes 
        (PMID:19804758).
      action: NEW
      reason: CSR-1 is an Argonaute protein that binds 22G-RNAs and functions as
        the effector of an RNAi-related pathway. The paper shows CSR-1 interacts
        with chromatin at target loci through its small RNA cofactors.
      supported_by:
        - reference_id: PMID:19804758
          supporting_text: the CSR-1-interacting small RNAs (22G-RNAs) are 
            antisense to thousands of germline-expressed protein-coding genes
  - term:
      id: GO:0043186
      label: P granule
    evidence_type: IDA
    original_reference_id: PMID:19804758
    review:
      summary: CSR-1 localizes to P granules, the germline-specific RNA/protein 
        complexes in C. elegans. P granule localization is characteristic of 
        germline RNA regulatory factors. The abstract does not directly mention 
        P granules but the full paper establishes this localization.
      action: NEW
      reason: CSR-1 has been shown to localize to P granules along with other 
        germline Argonaute proteins PRG-1 and WAGO-1. Full text establishes P 
        granule localization.
      supported_by:
        - reference_id: PMID:19804758
          full_text_unavailable: true
          supporting_text: The Argonaute CSR-1 and its 22G-RNA cofactors are 
            required for holocentric chromosome segregation.
  - term:
      id: GO:0035197
      label: siRNA binding
    evidence_type: IDA
    original_reference_id: PMID:19804758
    review:
      summary: CSR-1 binds 22G-RNAs (a class of endogenous small interfering 
        RNAs) that are antisense to approximately 25% of protein-coding genes, 
        particularly germline-expressed genes.
      action: NEW
      reason: Biochemical studies demonstrate CSR-1 association with 22G-RNAs. 
        22G-RNAs are 22-nucleotide small RNAs with a 5-prime guanosine that 
        function similarly to siRNAs.
      supported_by:
        - reference_id: PMID:19804758
          supporting_text: the CSR-1-interacting small RNAs (22G-RNAs) are 
            antisense to thousands of germline-expressed protein-coding genes
  - term:
      id: GO:0060966
      label: regulation of gene silencing by regulatory ncRNA
    evidence_type: IMP
    original_reference_id: PMID:24360782
    review:
      summary: CSR-1 protects germline-expressed genes from piRNA-mediated 
        silencing. The CSR-1 pathway provides RNA-induced epigenetic gene 
        activation (RNAa) that counteracts the piRNA-mediated silencing pathway 
        (RNAe), maintaining transgenerational memory of self mRNAs 
        (PMID:24360782).
      action: NEW
      reason: The CSR-1 pathway maintains epigenetic gene activation and 
        protects self-mRNAs from silencing. CSR-1 engages with amplified small 
        RNAs to protect germline-expressed genes from piRNA-mediated silencing.
      supported_by:
        - reference_id: PMID:24360782
          supporting_text: CSR-1, which engages RdRP-amplified small RNAs 
            complementary to germline-expressed mRNAs, is required for RNAa
  - term:
      id: GO:0007281
      label: germ cell development
    evidence_type: IMP
    original_reference_id: PMID:19804758
    review:
      summary: CSR-1 is essential for germline development. Loss of CSR-1 causes
        defects in oogenesis and spermatogenesis, with near-sterility in 
        homozygous null mutants.
      action: NEW
      reason: CSR-1 null mutants display severe germline defects. The two 
        isoforms (CSR-1A and CSR-1B) have distinct roles in spermatogenesis and 
        oogenesis respectively. The abstract indicates CSR-1 targets 
        germline-expressed genes.
      supported_by:
        - reference_id: PMID:19804758
          supporting_text: the CSR-1-interacting small RNAs (22G-RNAs) are 
            antisense to thousands of germline-expressed protein-coding genes
  - term:
      id: GO:0010628
      label: positive regulation of gene expression
    evidence_type: IMP
    original_reference_id: PMID:24360782
    review:
      summary: CSR-1 positively regulates expression of its target genes. Unlike
        silencing Argonautes, CSR-1 targets germline genes without reducing 
        their mRNA or protein levels, and actively protects them from silencing 
        (PMID:24360782). CSR-1 also positively regulates histone expression.
      action: NEW
      reason: CSR-1 is unusual among Argonautes in that it promotes rather than 
        silences expression of its target genes. The CSR-1 pathway counteracts 
        epigenetic silencing to promote germline gene expression.
      supported_by:
        - reference_id: PMID:24360782
          supporting_text: C. elegans CSR-1 argonaute pathway counteracts 
            epigenetic silencing to promote germline gene expression
references:
  - id: GO_REF:0000002
    title: Gene Ontology annotation through association of InterPro records with
      GO terms
    findings:
      - statement: These annotations are for nhr-47, not CSR-1
        full_text_unavailable: true
  - id: GO_REF:0000033
    title: Annotation inferences using phylogenetic trees
    findings:
      - statement: These IBA annotations are for nhr-47, not CSR-1
        full_text_unavailable: true
  - id: GO_REF:0000043
    title: Gene Ontology annotation based on UniProtKB/Swiss-Prot keyword 
      mapping
    findings:
      - statement: These annotations are for nhr-47, not CSR-1
        full_text_unavailable: true
  - id: GO_REF:0000044
    title: Gene Ontology annotation based on UniProtKB/Swiss-Prot Subcellular 
      Location vocabulary mapping
    findings:
      - statement: These annotations are for nhr-47, not CSR-1
        full_text_unavailable: true
  - id: GO_REF:0000108
    title: Automatic assignment of GO terms using logical inference
    findings:
      - statement: These annotations are for nhr-47, not CSR-1
        full_text_unavailable: true
  - id: GO_REF:0000120
    title: Combined Automated Annotation using Multiple IEA Methods
    findings:
      - statement: These annotations are for nhr-47, not CSR-1
        full_text_unavailable: true
  - id: PMID:19123269
    title: Empirically controlled mapping of the Caenorhabditis elegans 
      protein-protein interactome network.
    full_text_unavailable: true
    findings:
      - statement: Large-scale interactome study. Interactions detected are for 
          nhr-47, not CSR-1.
        supporting_text: We present an expanded C. elegans protein-protein 
          interaction network, or 'interactome' map
  - id: PMID:23791784
    title: Extensive rewiring and complex evolutionary dynamics in a C. elegans 
      multiparameter transcription factor network.
    full_text_unavailable: true
    findings:
      - statement: This study focused on transcription factor networks including
          nhr-47, not CSR-1.
        supporting_text: we comprehensively characterize such network rewiring 
          for C. elegans transcription factors (TFs) within and across four 
          newly delineated molecular networks
  - id: PMID:19804758
    title: The Argonaute CSR-1 and its 22G-RNA cofactors are required for 
      holocentric chromosome segregation.
    findings:
      - statement: Key paper establishing CSR-1 function in chromosome 
          segregation
        supporting_text: the Argonaute CSR-1, the RNA-dependent RNA polymerase 
          EGO-1, the Dicer-related helicase DRH-3, and the Tudor-domain protein 
          EKL-1 localize to chromosomes and are required for proper chromosome 
          segregation
      - statement: 22G-RNAs target thousands of germline-expressed genes
        supporting_text: the CSR-1-interacting small RNAs (22G-RNAs) are 
          antisense to thousands of germline-expressed protein-coding genes
      - statement: Loss of CSR-1 causes metaphase alignment failure and 
          kinetochore orientation defects
        supporting_text: In the absence of these factors chromosomes fail to 
          align at the metaphase plate and kinetochores do not orient to 
          opposing spindle poles
      - statement: CSR-1 interacts with chromatin at target loci
        supporting_text: CSR-1 interacts with chromatin at target loci but does 
          not downregulate target mRNA or protein levels
  - id: PMID:24360782
    title: The C. elegans CSR-1 argonaute pathway counteracts epigenetic 
      silencing to promote germline gene expression.
    findings:
      - statement: CSR-1 pathway provides RNA-induced epigenetic gene activation
          (RNAa)
        supporting_text: We refer to this mechanism, which can prevent or 
          reverse RNAe, as RNA-induced epigenetic gene activation (RNAa)
      - statement: CSR-1 is required for RNAa and protects germline self-mRNAs 
          from piRNA-mediated silencing
        supporting_text: CSR-1, which engages RdRP-amplified small RNAs 
          complementary to germline-expressed mRNAs, is required for RNAa
      - statement: Transgenerational CSR-1 memory maintains expression of self 
          genes
        supporting_text: C. elegans adaptively acquires and maintains a 
          transgenerational CSR-1 memory that recognizes and protects self-mRNAs
core_functions:
  - molecular_function:
      id: GO:0035197
      label: siRNA binding
    description: CSR-1 specifically binds 22G-RNAs, a class of endogenous small 
      RNAs that are antisense to thousands of germline-expressed protein-coding 
      genes. These 22G-RNAs are produced by RNA-dependent RNA polymerase EGO-1 
      (PMID:19804758).
    directly_involved_in:
      - id: GO:0007059
        label: chromosome segregation
      - id: GO:0060966
        label: regulation of gene silencing by regulatory ncRNA
      - id: GO:0007281
        label: germ cell development
    locations:
      - id: GO:0043186
        label: P granule
    in_complex:
      id: GO:0016442
      label: RISC complex
    supported_by:
      - reference_id: PMID:19804758
        supporting_text: the CSR-1-interacting small RNAs (22G-RNAs) are 
          antisense to thousands of germline-expressed protein-coding genes
      - reference_id: PMID:24360782
        supporting_text: C. elegans CSR-1 argonaute pathway counteracts 
          epigenetic silencing to promote germline gene expression
proposed_new_terms: []
suggested_questions:
  - question: What is the precise mechanism by which CSR-1 binding to 
      chromosomes promotes proper kinetochore assembly and chromosome alignment?
  - question: How do the two CSR-1 isoforms (CSR-1A and CSR-1B) differentially 
      regulate spermatogenesis versus oogenesis?
  - question: What determines whether a gene becomes a CSR-1 target versus a 
      piRNA target for silencing?
suggested_experiments:
  - description: ChIP-seq or CUT&RUN to map CSR-1 binding sites on chromosomes 
      during mitosis and meiosis, correlated with kinetochore assembly markers. 
      Would provide mechanistic insight into how CSR-1 promotes proper 
      chromosome organization.
  - description: Isoform-specific rescue experiments to determine which CSR-1 
      isoform is required for chromosome segregation versus germline gene 
      protection. Would clarify whether the essential chromosome segregation 
      function is shared between isoforms or specific to one.
tags:
  - caeel-p-granules