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A mammalian tripartite enhancer cluster controls hypothalamic Pomc expression, food intake, and body weight.
Rojo, Daniela; Hael, Clara E; Soria, Agustina; de Souza, Flávio S J; Low, Malcolm J; Franchini, Lucía F; Rubinstein, Marcelo.
Afiliação
  • Rojo D; Instituto de Investigaciones en Ingeniería Genética y Biología Molecular, Consejo Nacional de Investigaciones Científicas y Técnicas, Buenos Aires 1428, Argentina.
  • Hael CE; Instituto de Investigaciones en Ingeniería Genética y Biología Molecular, Consejo Nacional de Investigaciones Científicas y Técnicas, Buenos Aires 1428, Argentina.
  • Soria A; Instituto de Investigaciones en Ingeniería Genética y Biología Molecular, Consejo Nacional de Investigaciones Científicas y Técnicas, Buenos Aires 1428, Argentina.
  • de Souza FSJ; Departamento de Fisiología, Biología Molecular y Celular, Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, Buenos Aires 1428, Argentina.
  • Low MJ; Departamento de Fisiología, Biología Molecular y Celular, Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, Buenos Aires 1428, Argentina.
  • Franchini LF; Instituto de Fisiología, Biología Molecular y Neurociencias, Universidad de Buenos Aires and Consejo Nacional de Investigaciones Científicas y Técnicas, Buenos Aires 1428, Argentina.
  • Rubinstein M; Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, MI 48105.
Proc Natl Acad Sci U S A ; 121(18): e2322692121, 2024 Apr 30.
Article em En | MEDLINE | ID: mdl-38652744
ABSTRACT
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 ERα. 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.
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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Peso Corporal / Peixe-Zebra / Pró-Opiomelanocortina / Elementos Facilitadores Genéticos / Ingestão de Alimentos / Hipotálamo Limite: Animals / Female / Humans / Male Idioma: En Revista: Proc Natl Acad Sci U S A Ano de publicação: 2024 Tipo de documento: Article País de afiliação: Argentina País de publicação: Estados Unidos

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Peso Corporal / Peixe-Zebra / Pró-Opiomelanocortina / Elementos Facilitadores Genéticos / Ingestão de Alimentos / Hipotálamo Limite: Animals / Female / Humans / Male Idioma: En Revista: Proc Natl Acad Sci U S A Ano de publicação: 2024 Tipo de documento: Article País de afiliação: Argentina País de publicação: Estados Unidos