RESUMEN
Understanding the mechanisms of activity-dependent gene transcription underlying adaptive behaviors is challenging at neuronal-subtype resolution. Using cell-type specific molecular analysis in agouti-related peptide (AgRP) neurons, we reveal that the profound hunger-induced transcriptional changes greatly depend on plant homeodomain finger protein 6 (PHF6), a transcriptional repressor enriched in AgRP neurons. Loss of PHF6 in the satiated mice results in a hunger-state-shifting transcriptional profile, while hunger fails to further induce a rapid and robust activity-dependent gene transcription in PHF6-deficient AgRP neurons. We reveal that PHF6 binds to the promoters of a subset of immediate-early genes (IEGs) and that this chromatin binding is dynamically regulated by hunger state. Depletion of PHF6 decreases hunger-driven feeding motivation and makes the mice resistant to body weight gain under repetitive fasting-refeeding conditions. Our work identifies a neuronal subtype-specific transcriptional repressor that modulates transcriptional profiles in different nutritional states and enables adaptive eating behavior.
Asunto(s)
Cromatina/metabolismo , Redes Reguladoras de Genes/genética , Hambre/fisiología , Neuronas/metabolismo , Proteínas Represoras/metabolismo , Proteína Relacionada con Agouti/metabolismo , Animales , Dieta , Regulación hacia Abajo/genética , Conducta Alimentaria , Ontología de Genes , Genes Inmediatos-Precoces , Hipotálamo/metabolismo , Ratones Endogámicos C57BL , Motivación , Regiones Promotoras Genéticas/genética , Unión Proteica , Proteínas Represoras/genética , Respuesta de Saciedad , Aumento de PesoRESUMEN
Histone methylation regulates chromatin structure and transcription. The recently identified histone demethylase lysine-specific demethylase 1 (LSD1) is chemically restricted to demethylation of only mono- and di- but not trimethylated histone H3 lysine 4 (H3K4me3). We show that the X-linked mental retardation (XLMR) gene SMCX (JARID1C), which encodes a JmjC-domain protein, reversed H3K4me3 to di- and mono- but not unmethylated products. Other SMCX family members, including SMCY, RBP2, and PLU-1, also demethylated H3K4me3. SMCX bound H3K9me3 via its N-terminal PHD (plant homeodomain) finger, which may help coordinate H3K4 demethylation and H3K9 methylation in transcriptional repression. Significantly, several XLMR-patient point mutations reduced SMCX demethylase activity and binding to H3K9me3 peptides, respectively. Importantly, studies in zebrafish and primary mammalian neurons demonstrated a role for SMCX in neuronal survival and dendritic development and a link to the demethylase activity. Our findings thus identify a family of H3K4me3 demethylases and uncover a critical link between histone modifications and XLMR.