BAF60a deficiency uncouples chromatin accessibility and cold sensitivity from white fat browning

• Published in: Nature communications Vol. 11; no. 1; pp. 2379 - 15
• Main Authors: Liu, Tongyu, Mi, Lin, Xiong, Jing, Orchard, Peter, Yu, Qi, Yu, Lei, Zhao, Xu-Yun, Meng, Zhuo-Xian, Parker, Stephen C. J., Lin, Jiandie D., Li, Siming
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 13.05.2020; Nature Publishing Group; Nature Portfolio
• Subjects: 13/1; 13/106; 13/109; 13/51; 13/89; 14; 14/28; 38/23; 38/61; 38/77; 631/136/142; 631/443/319/2723; 82/29; 82/83; Accessibility; Activation; Adipocytes; Adipocytes, Brown - drug effects; Adipocytes, Brown - metabolism; Adipocytes, Brown - ultrastructure; Adipose tissue; Adipose Tissue, Beige - metabolism; Adipose Tissue, Brown - drug effects; Adipose Tissue, Brown - metabolism; Adipose Tissue, White - drug effects; Adipose Tissue, White - metabolism; Adrenocorticotropic hormone; Adrenocorticotropic Hormone - pharmacology; Animals; Basic Helix-Loop-Helix Transcription Factors - metabolism; Binding sites; Binding Sites - genetics; Body fat; Browning; Cells, Cultured; Chromatin - genetics; Chromatin - metabolism; Chromatin remodeling; Chromosomal Proteins, Non-Histone - deficiency; Chromosomal Proteins, Non-Histone - genetics; Cold Temperature; Deactivation; Gene expression; Gene Expression - drug effects; Genomes; Humanities and Social Sciences; Inactivation; Membrane Proteins - genetics; Membrane Proteins - metabolism; Mice, Inbred C57BL; Mice, Knockout; Mice, Transgenic; multidisciplinary; Oxidation; Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha - metabolism; Pituitary; Pituitary hormones; Science; Science (multidisciplinary); Thermogenesis; Thermogenesis - drug effects; Thermogenesis - genetics; Transcription
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-020-16148-1

Brown and beige fat share a remarkably similar transcriptional program that supports fuel oxidation and thermogenesis. The chromatin-remodeling machinery that governs genome accessibility and renders adipocytes poised for thermogenic activation remains elusive. Here we show that BAF60a, a subunit of the SWI/SNF chromatin-remodeling complexes, serves an indispensable role in cold-induced thermogenesis in brown fat. BAF60a maintains chromatin accessibility at PPARγ and EBF2 binding sites for key thermogenic genes. Surprisingly, fat-specific BAF60a inactivation triggers more pronounced cold-induced browning of inguinal white adipose tissue that is linked to induction of MC2R, a receptor for the pituitary hormone ACTH. Elevated MC2R expression sensitizes adipocytes and BAF60a-deficient adipose tissue to thermogenic activation in response to ACTH stimulation. These observations reveal an unexpected dichotomous role of BAF60a-mediated chromatin remodeling in transcriptional control of brown and beige gene programs and illustrate a pituitary-adipose signaling axis in the control of thermogenesis. The regulatory networks that govern chromatin accessibility and gene expression in brown and beigeadipocytes remain to be fully elucidated. Here the authors use fat-specific inactivation of BAF60a toreveal a differential role for this chromatin remodeling factor in brown fat thermogenesis and coldinduced browning of inguinal fat.