A Functionally Conserved Enhancer is Critical for PGC1A Expression and Thermogenesis in Brown Fat

ABSTRACT Brown adipose tissue (BAT) undergoes progressive age‐related involution into white adipose tissue (WAT), yet the epigenetic mechanisms underlying BAT whitening remain unclear. This study investigates the transcriptomic dynamics of goat perirenal adipose tissue (PRAT) across four postnatal stages and profiles active histone modifications and chromatin accessibility in PRAT at postnatal day 1 (BAT) and day 90 (WAT). PRAT whitening coincides with reduced enrichment of active histone marks and decreased chromatin accessibility at genes involved in thermogenesis and mitochondrial function, critical for maintaining brown adipocyte identity. Integration of high‐resolution PGC1A chromatin interaction mapping identifies two BAT‐specific active enhancers, PGC1A‐En1 and PGC1A‐En2, which exhibit additive effects and are further activated under cold stimulation. Functional repression of PGC1A‐En1 and/or PGC1A‐En2 in goat brown adipocytes reduces PGC1A expression and impairs thermogenic capacity, highlighting the pivotal role of PGC1A‐En1. Consistently, lentivirus‐mediated repression of the conserved mouse Pgc1a‐En1 in vivo decreases Pgc1a expression and attenuates cold‐induced thermogenesis in BAT. Notably, the conserved PGC1A‐hEn1 also functions as a critical regulatory element required for PGC1A expression and thermogenic activation in human brown adipocytes. These findings elucidate epigenetic mechanisms controlling BAT activity and identify conserved enhancer elements as potential therapeutic targets for metabolic disorders.