Conserved Noncoding Cis-Elements Associated with Hibernation Modulate Metabolic and Behavioral Adaptations in Mice [CUT&Run]
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE295251 | GEO | 2025/09/02
REPOSITORIES: GEO
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Project description:Conserved cis-elements tied to hibernator evolution affect diverse metabolic traits in mice.
2025-09-02 | GSE295250 | GEO
Project description:Our study elucidates functional roles for conserved cis-elements associated with the evolution of mammalian hibernation. Genomic analyses found topologically associated domains (TADs) that disproportionately accumulated convergent genomic changes in hibernators, including the TAD for the Fat Mass & Obesity (Fto) locus. Some hibernation-linked cis-elements in this TAD form regulatory contacts with multiple neighboring genes. Knockout mice for these cis-elements exhibit Fto, Irx3, and Irx5 gene expression changes, impacting hundreds of genes downstream. Profiles of pre-torpor, torpor, and post-torpor phenotypes found distinct roles for each cis-element in metabolic control, while a high caloric diet uncovered different obesogenic effects. One cis-element promoting a lean phenotype influences foraging behaviors throughout life, affecting specific behavioral sequences. Thus, convergent evolution in hibernators pinpoints functional genetic mechanisms of mammalian metabolic control.
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Project description:This SuperSeries is composed of the SubSeries listed below.
2025-09-02 | GSE295376 | GEO
Project description:Conserved Noncoding Cis-Elements Associated with Hibernation Modulate Metabolic and Behavioral Adaptations in Mice
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Project description:Comparative genomic studies have identified thousands of conserved noncoding elements (CNEs) in the mammalian genome, many of which have been reported to exert cis-regulatory activity. We analyzed ∼5,500 pairs of adjacent CNEs in the human genome and found that despite divergence at the nucleotide sequence level, the inter-CNE distances of the pairs are under strong evolutionary constraint, with inter-CNE sequences featuring significantly lower transposon densities than expected. Further, we show that different degrees of conservation of the inter-CNE distance are associated with distinct cis-regulatory functions at the CNEs. Specifically, the CNEs in pairs with conserved and mildly contracted inter-CNE sequences are the most likely to represent active or poised enhancers. In contrast, CNEs in pairs with extremely contracted or expanded inter-CNE sequences are associated with no cis-regulatory activity. Furthermore, we observed that functional CNEs in a pair have very similar epigenetic profiles, hinting at a functional relationship between them. Taken together, our results support the existence of epistatic interactions between adjacent CNEs that are distance-sensitive and disrupted by transposon insertions and deletions, and contribute to our understanding of the selective forces acting on cis-regulatory elements, which are crucial for elucidating the molecular mechanisms underlying adaptive evolution and human genetic diseases.
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Project description:HOTAIR was proposed to regulate either HoxD cluster genes in trans or HoxC cluster genes in cis, a mechanism that remains unclear. We have identified a 32-nucleotide conserved noncoding element (CNE) as HOTAIR ancient sequence that likely originated at the root of vertebrate. The second round of whole-genome duplication resulted in one copy of the CNE within HOTAIR and another copy embedded in noncoding transcript of HOXD11. Paralogous CNEs underwent compensatory mutations, exhibit sequence complementarity with respect to transcripts directionality, and have high affinity in vitro. The HOTAIR CNE resembled a poised enhancer in stem cells and an active enhancer in HOTAIR-expressing cells. HOTAIR expression is positively correlated with HOXC11 in cis and negatively correlated with HOXD11 in trans. We propose a dual modality of HOTAIR regulation where transcription of HOTAIR and its embedded enhancer regulates HOXC11 in cis and sequence complementarity between paralogous CNEs suggests HOXD11 regulation in trans.
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