tra-1

Gene Description

Cbr-TRA-1 is the Caenorhabditis briggsae ortholog of the GLI/Ci-family C2H2 zinc-finger transcription factor TRA-1, the terminal global regulator of the nematode sex-determination pathway. The protein contains five tandem C2H2 zinc fingers (fingers 3-5 mediating sequence-specific DNA binding) and recognizes GLI-type cis-regulatory elements at target promoters. TRA-1 acts predominantly as a sequence-specific transcriptional repressor that promotes female (and hermaphrodite somatic) development by silencing male-fate genes; characterized targets include ceh-30 (whose repression eliminates CEM male sensory neurons), dmd-3 (controlling male tail-tip morphogenesis), and genes governing male somatic and neuronal differentiation. TRA-1 also has a context-dependent activating role; together with the Tip60/TRR-1 histone-acetyltransferase complex it activates fog-3 to specify the sperm/oocyte decision. TRA-1 is principally nuclear but also cytoplasmic, and its activity is modulated by regulated CRM1-dependent nuclear export coupled to binding of the tra-2 mRNA; it also physically interacts with the intracellular MX domain of the TRA-2 membrane protein. Two splice isoforms are produced, of which only the longer (isoform a, Tra-1L) is thought to bind DNA. As an evolutionary comparator to C. elegans TRA-1, the gene is notable for the unusually high sequence divergence of tra-1 between Caenorhabditis species.

Existing Annotations Review

GO Term	Evidence	Action	Reason
GO:0005634 nucleus	IBA GO_REF:0000033	ACCEPT	Summary: TRA-1 is a transcription factor that acts in the nucleus, consistent with the GLI/Ci family phylogenetic inference and with experimental evidence that TRA-1 is nuclear (and that its nuclear level is sex-specifically regulated by export). Correct and core to its function as a DNA-binding TF.
GO:0000981 DNA-binding transcription factor activity, RNA polymerase II-specific	IBA GO_REF:0000033	ACCEPT	Summary: This is the core molecular function of TRA-1, a GLI/Ci-family C2H2 zinc-finger transcription factor that binds sequence-specific cis-regulatory elements to regulate RNA polymerase II transcription of sex-determination target genes. Well supported by the family-wide IBA inference and by C. elegans experimental data on direct target regulation.
GO:0000122 negative regulation of transcription by RNA polymerase II	IBA GO_REF:0000033	ACCEPT	Summary: TRA-1 acts predominantly as a transcriptional repressor of male-fate genes (e.g. ceh-30, dmd-3) to promote female/hermaphrodite development. This repressor role is the central regulatory activity of TRA-1 and is consistent with the GLI/Ci family. Accepted as a core process.
GO:0045944 positive regulation of transcription by RNA polymerase II	IBA GO_REF:0000033	ACCEPT	Summary: TRA-1 also has a context-dependent activating role, notably activating fog-3 together with the TRR-1/Tip60 HAT complex to control the sperm/oocyte decision (PubMed:24098152). Activation is a genuine but secondary aspect of TRA-1 function relative to its dominant repressor role; the term is valid.
GO:0000978 RNA polymerase II cis-regulatory region sequence-specific DNA binding	IBA GO_REF:0000033	ACCEPT	Summary: TRA-1 binds sequence-specific GLI-type cis-regulatory DNA elements via its C2H2 zinc fingers (fingers 3-5), e.g. at the fog-3 promoter and an intronic regulatory site in ceh-30. This sequence-specific DNA-binding activity is core and well supported by the family inference.
GO:0000977 RNA polymerase II transcription regulatory region sequence-specific DNA binding	IEA GO_REF:0000002	ACCEPT	Summary: InterPro-based electronic annotation of sequence-specific regulatory DNA binding, consistent with the GLI/Ci zinc-finger architecture and with the curated IBA DNA-binding terms. Correct; this is a slightly more general sibling of the IBA cis-regulatory binding term and is retained.
GO:0005634 nucleus	IEA GO_REF:0000120	ACCEPT	Summary: Nuclear localization is correct for this transcription factor and is supported experimentally and by the IBA assignment. Redundant with the IBA nucleus annotation but valid.
GO:0005737 cytoplasm	IEA GO_REF:0000044	KEEP AS NON CORE	Summary: Cytoplasmic localization is documented; TRA-1 partitions between nucleus and cytoplasm and is subject to regulated CRM1-dependent nuclear export coupled to tra-2 mRNA binding, which lowers nuclear (transcriptional) activity. Valid as a non-core localization that is mechanistically relevant to regulation rather than to the core DNA-binding TF function.
GO:0019099 female germ-line sex determination	IEA GO_REF:0000117	KEEP AS NON CORE	Summary: TRA-1 is the terminal regulator of the sex-determination pathway and controls germline sexual fate (including the sperm/oocyte decision via fog-3). Female germ-line sex determination is a genuine downstream process role. Retained as a non-core developmental-process annotation distinct from the core molecular DNA-binding/TF activity.
GO:0019101 female somatic sex determination	IEA GO_REF:0000117	KEEP AS NON CORE	Summary: TRA-1 promotes female somatic development by repressing male-fate genes in the soma (e.g. ceh-30, dmd-3, male neuronal/morphological programs). This is a central biological role of TRA-1. Retained as a (non-core relative to the molecular function) developmental-process annotation.
GO:0005634 nucleus	ISS GO_REF:0000024	ACCEPT	Summary: Nuclear localization inferred by sequence similarity from C. elegans TRA-1 (UniProtKB:P34708). Correct for this transcription factor; redundant with the IBA/IEA nucleus annotations.
GO:0005737 cytoplasm	ISS GO_REF:0000024	KEEP AS NON CORE	Summary: Cytoplasmic localization inferred by similarity from C. elegans TRA-1. Consistent with the documented nucleocytoplasmic partitioning and regulated nuclear export. Non-core localization.
GO:0005634 nucleus	ISS PMID:11703944 RNA-Regulated TRA-1 nuclear export controls sexual fate.	ACCEPT	Summary: Nuclear localization inferred by similarity, supported by the cited study on RNA-regulated TRA-1 nuclear export, which reports nuclear TRA-1 (higher in hermaphrodites; increased in males upon export inhibition). Correct and core.
GO:0005737 cytoplasm	ISS PMID:11703944 RNA-Regulated TRA-1 nuclear export controls sexual fate.	KEEP AS NON CORE	Summary: Cytoplasmic localization inferred by similarity, consistent with the cited study showing CRM1-dependent nuclear export of TRA-1 (coexport of a TRA-1/tra-2 mRNA complex reduces nuclear activity), which implies a cytoplasmic pool. Valid non-core localization mechanistically linked to regulation.
GO:0005515 protein binding	IPI PMID:11250902 The TRA-1 transcription factor binds TRA-2 to regulate sexua...	KEEP AS NON CORE	Summary: Experimental IPI annotation supported by demonstration that TRA-1 binds the intracellular MX regulatory domain of the TRA-2 membrane protein (interaction conserved in C. briggsae, with WITH/FROM UniProtKB:Q17307 = Cbr TRA-2). The interaction is real and functionally important, but the bare 'protein binding' term is uninformative as a core molecular function. Retained as a valid but non-core annotation; the specific interacting partner is TRA-2.
GO:0019099 female germ-line sex determination	TAS PMID:11250902 The TRA-1 transcription factor binds TRA-2 to regulate sexua...	KEEP AS NON CORE	Summary: Author-stated (TAS) role of TRA-1 in promoting female germline fate; the cited paper places tra-1 as the terminal regulator promoting female fates and shows its TRA-2 interaction regulating spermatogenesis. Genuine developmental-process role, retained as non-core relative to the molecular function.
GO:0019101 female somatic sex determination	TAS PMID:11250902 The TRA-1 transcription factor binds TRA-2 to regulate sexua...	KEEP AS NON CORE	Summary: Author-stated (TAS) role of TRA-1 in promoting female somatic fates, consistent with its position as terminal regulator of the sex-determination pathway. Genuine but non-core developmental-process annotation.

Gene Description

Existing Annotations Review

Core Functions

Sequence-specific binding of RNA polymerase II cis-regulatory DNA elements via tandem C2H2 zinc fingers (fingers 3-5 mediate site selection), the DNA-recognition activity underlying TRA-1 target-gene regulation.

References

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