Life Sciences Institute and Department of Cell and Developmental Biology, University of Michigan Medical Center, Ann Arbor, MI 48109
Brown fat thermogenesis is important for cold defense and systemic energy balance. The activation of the thermogenic gene program during development and in response to cold requires global reconfiguration of chromatin structure. Here we demonstrate that BAF60a, a component of SWI/SNF chromatin-remodeling complex, is indispensable for cold-induced thermogenesis. Mice with adipose tissue-specific inactivation of BAF60a exhibited impaired thermogenic gene expression and were exquisitely cold-sensitive. Assay for Transposase-Accessible Chromatin using sequencing (ATAC) revealed that chromatin accessibility of many brown fat-enriched genes was markedly reduced by Baf60a deficiency. Motif enrichment analysis indicated that these BAF60a-dependent chromatin regions are highly enriched for binding sites for PPARγ, EBF2, and C/EBPβ, key transcriptional regulators of thermogenic gene expression, suggesting that BAF60a likely serves an important role in orchestrating the thermogenic chromatin state. Adipose tissue inactivation of BAF60a augmented browning of inguinal adipose tissue following cold acclimation. Mechanistically, this browning response was linked to compensatory activation of the ACTH/Melanocortin 2 Receptor signaling. Our studies outline a mechanism of global control of chromatin accessibility during thermogenesis and reveal differential role of BAF60a in brown and beige fat biogenesis.
S. Li: None. T. Liu: None. L. Mi: None. Z. Meng: None. J. Lin: None.