SIM1 (single-minded homolog 1) encodes a class I bHLH-PAS transcription factor that binds DNA and regulates RNA polymerase II transcription as an obligate heterodimer with a class II bHLH-PAS partner, ARNT or (in the hypothalamus) ARNT2. It is expressed in the developing paraventricular (PVN), anterior periventricular and supraoptic nuclei of the hypothalamus, where it is required for terminal differentiation of oxytocin, vasopressin, TRH, CRH and somatostatin neuroendocrine neurons, acting upstream of BRN2 (POU3F2) and SIM2; it is also expressed in developing kidney, somites and other tissues. SIM1-expressing PVN neurons lie downstream of leptin-melanocortin (MC4R) signalling in the control of food intake, and heterozygous loss of SIM1 in mice and humans causes hyperphagic early-onset obesity, sometimes with Prader-Willi-like features.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0000785 chromatin | ISA GO_REF:0000113 | KEEP AS NON CORE | Summary: Chromatin location inferred from TF class membership; expected for a sequence-specific DNA-binding factor. Reason: Generic consequence of DNA binding; nucleus is the more established location. |
| GO:0000977 RNA polymerase II transcription regulatory region sequence-specific DNA binding | IBA GO_REF:0000033 | ACCEPT | Summary: Phylogenetic inference of RNA polymerase II regulatory-region sequence-specific DNA binding for the SIM clade (Drosophila sim, mouse Sim1/Sim2). Reason: bHLH-PAS SIM1 binds DNA as a heterodimer with ARNT/ARNT2. Supporting Evidence: PMID:23778136 One of the aryl hydrocarbon receptor nuclear translocators, either ARNT or ARNT2, is required as a dimerization partner for SIM1 to function as a transcription factor, with mouse knockout studies suggesting that ARNT2 is the in vivo partner in the hypothalamus |
| GO:0000981 DNA-binding transcription factor activity, RNA polymerase II-specific | IBA GO_REF:0000033 | ACCEPT | Summary: Phylogenetic inference of RNA polymerase II-specific DNA-binding transcription factor activity. Reason: Core activity; SIM1 regulates reporter transcription with ARNT/ARNT2 and loss-of-function variants reduce it. Supporting Evidence: PMID:23778136 One of the aryl hydrocarbon receptor nuclear translocators, either ARNT or ARNT2, is required as a dimerization partner for SIM1 to function as a transcription factor, with mouse knockout studies suggesting that ARNT2 is the in vivo partner in the hypothalamus PMID:23778136 We then assessed functional effects of the 8 substitutions on SIM1 transcriptional activities in stable cell lines using luciferase gene reporter assays. |
| GO:0000981 DNA-binding transcription factor activity, RNA polymerase II-specific | ISA GO_REF:0000113 | ACCEPT | Summary: TF-class based assignment of RNA polymerase II-specific DNA-binding TF activity. Reason: Core activity. Supporting Evidence: PMID:23778136 One of the aryl hydrocarbon receptor nuclear translocators, either ARNT or ARNT2, is required as a dimerization partner for SIM1 to function as a transcription factor, with mouse knockout studies suggesting that ARNT2 is the in vivo partner in the hypothalamus |
| GO:0001657 ureteric bud development | IEA GO_REF:0000107 | UNDECIDED | Summary: Ortholog-based transfer from mouse Sim1 of ureteric bud development; Sim1 is expressed in the mesonephric duct and developing kidney, but a functional requirement could not be verified here. Reason: Expression supports a possible role, but the mouse functional evidence behind this transfer was not available for review. Supporting Evidence: PMID:8812055 Both murine Sim genes are also expressed in the developing kidney. |
| GO:0003677 DNA binding | IEA GO_REF:0000002 | MODIFY | Summary: Generic DNA binding from InterPro; correct but less specific than the sequence-specific Pol II regulatory region term. Reason: Use the more specific DNA-binding term. Proposed replacements: RNA polymerase II transcription regulatory region sequence-specific DNA binding Supporting Evidence: PMID:23778136 One of the aryl hydrocarbon receptor nuclear translocators, either ARNT or ARNT2, is required as a dimerization partner for SIM1 to function as a transcription factor, with mouse knockout studies suggesting that ARNT2 is the in vivo partner in the hypothalamus |
| GO:0003677 DNA binding | TAS PMID:8812055 Expression patterns of two murine homologs of Drosophila sin... | MODIFY | Summary: Author statement from the mouse Sim1/Sim2 expression paper that sim encodes a transcriptional regulator; generic DNA binding. Reason: Use the more specific DNA-binding term. Proposed replacements: RNA polymerase II transcription regulatory region sequence-specific DNA binding Supporting Evidence: PMID:23778136 One of the aryl hydrocarbon receptor nuclear translocators, either ARNT or ARNT2, is required as a dimerization partner for SIM1 to function as a transcription factor, with mouse knockout studies suggesting that ARNT2 is the in vivo partner in the hypothalamus |
| GO:0003700 DNA-binding transcription factor activity | IEA GO_REF:0000002 | MODIFY | Summary: Generic DNA-binding TF activity from InterPro; correct. Reason: SIM1 is an RNA polymerase II-specific transcription factor; use the more specific term. Proposed replacements: DNA-binding transcription factor activity, RNA polymerase II-specific Supporting Evidence: PMID:23778136 One of the aryl hydrocarbon receptor nuclear translocators, either ARNT or ARNT2, is required as a dimerization partner for SIM1 to function as a transcription factor, with mouse knockout studies suggesting that ARNT2 is the in vivo partner in the hypothalamus |
| GO:0003700 DNA-binding transcription factor activity | TAS PMID:8812055 Expression patterns of two murine homologs of Drosophila sin... | MODIFY | Summary: Author statement (mouse Sim homolog paper) of transcription-factor activity. Reason: Use the RNA polymerase II-specific term. Proposed replacements: DNA-binding transcription factor activity, RNA polymerase II-specific Supporting Evidence: PMID:23778136 One of the aryl hydrocarbon receptor nuclear translocators, either ARNT or ARNT2, is required as a dimerization partner for SIM1 to function as a transcription factor, with mouse knockout studies suggesting that ARNT2 is the in vivo partner in the hypothalamus |
| GO:0003700 DNA-binding transcription factor activity | TAS PMID:9199934 Cloning of two human homologs of the Drosophila single-minde... | MODIFY | Summary: Author statement from human SIM1/SIM2 cloning paper; generic DNA-binding TF activity. Reason: Use the RNA polymerase II-specific term. Proposed replacements: DNA-binding transcription factor activity, RNA polymerase II-specific Supporting Evidence: PMID:23778136 One of the aryl hydrocarbon receptor nuclear translocators, either ARNT or ARNT2, is required as a dimerization partner for SIM1 to function as a transcription factor, with mouse knockout studies suggesting that ARNT2 is the in vivo partner in the hypothalamus |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | MODIFY | Summary: HuRI binary interaction with ARNT2, the established in vivo heterodimerization partner of SIM1. Reason: The interaction is the functional bHLH-PAS heterodimer; protein heterodimerization activity is the informative term. Proposed replacements: protein heterodimerization activity Supporting Evidence: PMID:10640708 we provide evidence that Sim1 and Arnt2 form dimers in vitro PMID:23778136 One of the aryl hydrocarbon receptor nuclear translocators, either ARNT or ARNT2, is required as a dimerization partner for SIM1 to function as a transcription factor, with mouse knockout studies suggesting that ARNT2 is the in vivo partner in the hypothalamus |
| GO:0005634 nucleus | IBA GO_REF:0000033 | ACCEPT | Summary: Phylogenetic is_active_in nucleus; correct for a transcription factor. Reason: Core location. Supporting Evidence: PMID:23778136 One of the aryl hydrocarbon receptor nuclear translocators, either ARNT or ARNT2, is required as a dimerization partner for SIM1 to function as a transcription factor, with mouse knockout studies suggesting that ARNT2 is the in vivo partner in the hypothalamus |
| GO:0005634 nucleus | IEA GO_REF:0000120 | ACCEPT | Summary: Electronic nucleus annotation; correct. Reason: Core location. Supporting Evidence: PMID:23778136 One of the aryl hydrocarbon receptor nuclear translocators, either ARNT or ARNT2, is required as a dimerization partner for SIM1 to function as a transcription factor, with mouse knockout studies suggesting that ARNT2 is the in vivo partner in the hypothalamus |
| GO:0006355 regulation of DNA-templated transcription | IEA GO_REF:0000120 | MODIFY | Summary: Generic regulation of DNA-templated transcription from InterPro/ARBA. Reason: SIM1 is a Pol II transcription factor; use the more specific process. Proposed replacements: regulation of transcription by RNA polymerase II Supporting Evidence: PMID:23778136 We then assessed functional effects of the 8 substitutions on SIM1 transcriptional activities in stable cell lines using luciferase gene reporter assays. |
| GO:0006357 regulation of transcription by RNA polymerase II | IBA GO_REF:0000033 | ACCEPT | Summary: Phylogenetic inference of regulation of transcription by RNA polymerase II. Reason: Core process at the molecular level. Supporting Evidence: PMID:23778136 We then assessed functional effects of the 8 substitutions on SIM1 transcriptional activities in stable cell lines using luciferase gene reporter assays. PMID:23778136 One of the aryl hydrocarbon receptor nuclear translocators, either ARNT or ARNT2, is required as a dimerization partner for SIM1 to function as a transcription factor, with mouse knockout studies suggesting that ARNT2 is the in vivo partner in the hypothalamus |
| GO:0007399 nervous system development | TAS PMID:9199934 Cloning of two human homologs of the Drosophila single-minde... | MODIFY | Summary: Author statement that SIM homologs act in neurogenesis; correct but very broad. The best-characterised role is terminal differentiation of hypothalamic neuroendocrine neurons. Reason: Replace with the specific developmental process demonstrated in Sim1-null mice. Proposed replacements: hypothalamus cell differentiation Supporting Evidence: PMID:9784500 At least five distinct types of secretory neurons, identified by the expression of oxytocin, vasopressin, thyrotropin-releasing hormone, corticotropin-releasing hormone, and somatostatin, are absent in the mutant PVN, aPV, and SON. PMID:9784500 we show that SIM1 controls the development of these secretory neurons at the final stages of their differentiation |
| GO:0046982 protein heterodimerization activity | IEA GO_REF:0000107 | ACCEPT | Summary: Ortholog-based transfer of protein heterodimerization activity (Sim1 with Arnt/Arnt2). Reason: Obligate heterodimerization with ARNT/ARNT2 is required for SIM1 function. Supporting Evidence: PMID:10640708 we provide evidence that Sim1 and Arnt2 form dimers in vitro PMID:23778136 One of the aryl hydrocarbon receptor nuclear translocators, either ARNT or ARNT2, is required as a dimerization partner for SIM1 to function as a transcription factor, with mouse knockout studies suggesting that ARNT2 is the in vivo partner in the hypothalamus |
| GO:0046982 protein heterodimerization activity | ISS GO_REF:0000024 | ACCEPT | Summary: ISS from mouse Sim1 of protein heterodimerization activity. Reason: As above. Supporting Evidence: PMID:10640708 we provide evidence that Sim1 and Arnt2 form dimers in vitro PMID:23778136 One of the aryl hydrocarbon receptor nuclear translocators, either ARNT or ARNT2, is required as a dimerization partner for SIM1 to function as a transcription factor, with mouse knockout studies suggesting that ARNT2 is the in vivo partner in the hypothalamus |
| GO:0046983 protein dimerization activity | IEA GO_REF:0000002 | MODIFY | Summary: Generic protein dimerization activity from bHLH/PAS InterPro domains. Reason: SIM1 specifically heterodimerizes with ARNT/ARNT2. Proposed replacements: protein heterodimerization activity Supporting Evidence: PMID:10640708 we provide evidence that Sim1 and Arnt2 form dimers in vitro |
| GO:0048731 system development | IEA GO_REF:0000117 | MODIFY | Summary: ARBA prediction of system development; correct but very general. Reason: The established developmental role is hypothalamic neuroendocrine cell differentiation. Proposed replacements: hypothalamus cell differentiation Supporting Evidence: PMID:9784500 At least five distinct types of secretory neurons, identified by the expression of oxytocin, vasopressin, thyrotropin-releasing hormone, corticotropin-releasing hormone, and somatostatin, are absent in the mutant PVN, aPV, and SON. |
| GO:0160108 animal gross anatomical part developmental process | IEA GO_REF:0000117 | MARK AS OVER ANNOTATED | Summary: ARBA prediction of animal gross anatomical part developmental process; uninformative grouping term. Reason: Too general to convey SIM1 biology; covered by the more specific hypothalamus cell differentiation. |
| GO:0021979 hypothalamus cell differentiation | IMP PMID:9784500 Development of neuroendocrine lineages requires the bHLH-PAS... | NEW | Summary: Sim1-null mice lack oxytocin, vasopressin, TRH, CRH and somatostatin neurons of the PVN, aPV and SON; SIM1 controls their terminal differentiation upstream of Brn2. Sim1 heterozygosity reduces PVN cell number and causes hyperphagic obesity, and human SIM1 loss of function causes obesity. Reason: SIM1 directly drives this differentiation programme as a transcription factor; mouse loss-of-function evidence, consistent with the human obesity phenotype. Supporting Evidence: PMID:9784500 At least five distinct types of secretory neurons, identified by the expression of oxytocin, vasopressin, thyrotropin-releasing hormone, corticotropin-releasing hormone, and somatostatin, are absent in the mutant PVN, aPV, and SON. PMID:9784500 we show that SIM1 controls the development of these secretory neurons at the final stages of their differentiation PMID:11448938 Sim1 heterozygous mice are viable but develop early-onset obesity, with increased linear growth, hyperinsulinemia and hyperleptinemia |
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Download this section (compressed HTML)Q: Postnatal CNS deletion of Sim1 in mouse is by itself sufficient to cause hyperphagic obesity, with reduced hypothalamic Oxt and PVN Mc4r and without global PVN hypocellularity or loss of the examined projections [PMID:20220015], so the postnatal role is separable from the developmental one. What remains open is the mechanism. Is the adult requirement direct transcriptional maintenance of Oxt and Mc4r in those neurons, or maintenance of the neuronal identity that keeps them expressed, and does the same hold in human carriers?
Suggested experts: hypothalamic neuroendocrinology experts
Q: Which SIM1:ARNT2 target genes in PVN neurons mediate the obesity phenotype?
Suggested experts: transcriptional regulation experts
Experiment: CUT&RUN for SIM1 and ARNT2 in human iPSC-derived PVN-like neurons combined with RNA-seq of SIM1 heterozygous lines.
Hypothesis: SIM1:ARNT2 directly regulates genes of the melanocortin-responsive PVN neuron programme (e.g. MC4R pathway components).
Type: genomics
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