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

Tongyu Liu; Lin Mi; Jing Xiong; Peter Orchard; Qi Yu; Lei Yu; Xu-Yun Zhao; Zhuo-Xian Meng; Stephen C J Parker; Jiandie D Lin; Siming Li

doi:10.1038/s41467-020-16148-1

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

Nat Commun. 2020 May 13;11(1):2379. doi: 10.1038/s41467-020-16148-1.

Authors

Tongyu Liu^#^{1

2}, Lin Mi^#¹, Jing Xiong¹, Peter Orchard^{2

3}, Qi Yu¹, Lei Yu¹, Xu-Yun Zhao¹, Zhuo-Xian Meng^{4

5}, Stephen C J Parker^{2

3}, Jiandie D Lin⁶, Siming Li⁷

Affiliations

¹ Life Sciences Institute and Department of Cell and Developmental Biology, University of Michigan, Ann Arbor, MI, 48109, USA.
² Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, MI, 48109, USA.
³ Department of Human Genetics, University of Michigan, Ann Arbor, MI, 48109, USA.
⁴ Department of Pathology and Pathophysiology, Key Laboratory of Disease Proteomics of Zhejiang Province, Hangzhou, Zhejiang, 310058, China.
⁵ Chronic Disease Research Institute of School of Public Health, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, 310058, China.
⁶ Life Sciences Institute and Department of Cell and Developmental Biology, University of Michigan, Ann Arbor, MI, 48109, USA. jdlin@umich.edu.
⁷ Life Sciences Institute and Department of Cell and Developmental Biology, University of Michigan, Ann Arbor, MI, 48109, USA. simingli@umich.edu.

^# Contributed equally.

Abstract

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.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Adipocytes, Brown / drug effects
Adipocytes, Brown / metabolism
Adipocytes, Brown / ultrastructure
Adipose Tissue, Beige / metabolism
Adipose Tissue, Brown / drug effects
Adipose Tissue, Brown / metabolism*
Adipose Tissue, White / drug effects
Adipose Tissue, White / metabolism*
Adrenocorticotropic Hormone / pharmacology
Animals
Basic Helix-Loop-Helix Transcription Factors / metabolism
Binding Sites / genetics
Cells, Cultured
Chromatin / genetics
Chromatin / metabolism*
Chromosomal Proteins, Non-Histone / deficiency*
Chromosomal Proteins, Non-Histone / genetics
Cold Temperature*
Gene Expression / drug effects
Membrane Proteins / genetics
Membrane Proteins / metabolism
Mice, Inbred C57BL
Mice, Knockout
Mice, Transgenic
Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha / metabolism
Thermogenesis / drug effects
Thermogenesis / genetics

Substances

Basic Helix-Loop-Helix Transcription Factors
Chromatin
Chromosomal Proteins, Non-Histone
Ebf2 protein, mouse
MRAP protein, mouse
Membrane Proteins
Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha
Smarcd1 protein, mouse
Adrenocorticotropic Hormone

Abstract

Publication types

MeSH terms

Substances

Grants and funding