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

Area of Science:

• Epigenetics
• Adipose tissue biology
• Metabolic regulation

Background:

• Brown adipose tissue (BAT) involutes with age, transitioning to white adipose tissue (WAT), a process poorly understood at the epigenetic level.
• Understanding the molecular mechanisms of BAT whitening is crucial for addressing metabolic disorders.

Purpose of the Study:

• To investigate the transcriptomic and epigenetic dynamics during goat perirenal adipose tissue (PRAT) development from BAT to WAT.
• To identify key regulatory elements controlling PGC1A expression and thermogenic function in BAT.
• To explore the therapeutic potential of conserved enhancer elements for metabolic diseases.

Main Methods:

• Transcriptomic analysis across four postnatal stages of goat PRAT.
• Profiling of active histone modifications and chromatin accessibility in PRAT at different developmental stages.
• High-resolution PGC1A chromatin interaction mapping.
• Functional repression of identified enhancers in goat and mouse brown adipocytes and in vivo.
• Investigation of conserved human enhancer function.

Main Results:

• PRAT whitening is associated with reduced active histone marks and chromatin accessibility at thermogenesis and mitochondrial genes.
• Two BAT-specific enhancers, PGC1A-En1 and PGC1A-En2, were identified, showing additive effects and activation by cold stimulation.
• Repression of PGC1A-En1 and PGC1A-En2 impairs PGC1A expression and thermogenic capacity in goat brown adipocytes.
• In vivo repression of the conserved mouse Pgc1a-En1 reduces Pgc1a expression and cold-induced thermogenesis.
• The conserved human PGC1A-hEn1 is essential for PGC1A expression and thermogenic activation in human brown adipocytes.

Conclusions:

• Epigenetic mechanisms, particularly conserved enhancer elements like PGC1A-En1, play a critical role in regulating BAT activity and thermogenesis.
• These enhancers are pivotal for maintaining brown adipocyte identity and function during development and in response to cold.
• Conserved enhancer elements represent promising therapeutic targets for metabolic disorders associated with impaired BAT function.