A mammalian tripartite enhancer cluster controls hypothalamic Pomc expression, food intake, and body weight

• 成果类型: Article
• 署名作者: Rojo, Daniela; Hael, Clara E.; Soria, Agustina; de Souza, Flavio S. J.; Low, Malcolm J.; Franchini, Lucia F.; Rubinstein, Marcelo
• 署名单位: Consejo Nacional de Investigaciones Cientificas y Tecnicas (CONICET); University of Buenos Aires; University of Buenos Aires; Consejo Nacional de Investigaciones Cientificas y Tecnicas (CONICET); University of Michigan System; University of Michigan; Stanford University
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-10929
• DOI: 10.1073/pnas.2322692121
• 发表日期: 2024-04-30
• 关键词: proopiomelanocortin gene; melanocortin neurons; phase-separation; pomc gene; obesity; EVOLUTION; transcription; expression; IDENTITY; Robustness

摘要

Food intake and energy balance are tightly regulated by a group of hypothalamic arcuate neurons expressing the proopiomelanocortin ( POMC) gene. In mammals, arcuate - specific POMC expression is driven by two cis - acting transcriptional enhancers known as nPE1 and nPE2. Because mutant mice lacking these two enhancers still showed hypothalamic Pomc mRNA, we searched for additional elements contributing to arcuate Pomc expression. By combining molecular evolution with reporter gene expression in transgenic zebrafish and mice, here, we identified a mammalian arcuate - specific Pomc enhancer that we named nPE3, carrying several binding sites also present in nPE1 and nPE2 for transcription factors known to activate neuronal Pomc expression, such as ISL1, NKX2.1, and ER alpha . We found that nPE3 originated in the lineage leading to placental mammals and remained under purifying selection in all mammalian orders, although it was lost in Simiiformes (monkeys, apes, and humans) following a unique segmental deletion event. Interestingly, ablation of nPE3 from the mouse genome led to a drastic reduction (>70%) in hypothalamic Pomc mRNA during development and only moderate (<33%) in adult mice. Comparison between double (nPE1 and nPE2) and triple (nPE1, nPE2, and nPE3) enhancer mutants revealed the relative contribution of nPE3 to hypothalamic Pomc expression and its importance in the control of food intake and adiposity in male and female mice. Altogether, these results demonstrate that nPE3 integrates a tripartite cluster of partially redundant enhancers that originated upon a triple convergent evolutionary process in mammals and that is critical for hypothalamic Pomc expression and body weight homeostasis.