EBF2 transcriptionally regulates brown adipogenesis via the histone reader DPF3 and the BAF chromatin remodeling complex

TY - JOUR

T1 - EBF2 transcriptionally regulates brown adipogenesis via the histone reader DPF3 and the BAF chromatin remodeling complex

AU - Shapira, Suzanne N

AU - Lim, Hee-Woong

AU - Rajakumari, Sona

AU - Sakers, Alexander P

AU - Ishibashi, Jeff

AU - Harms, Matthew J

AU - Won, Kyoung-Jae

AU - Seale, Patrick

N1 - © 2017 Shapira et al.; Published by Cold Spring Harbor Laboratory Press.

PY - 2017/4/1

Y1 - 2017/4/1

N2 - The transcription factor early B-cell factor 2 (EBF2) is an essential mediator of brown adipocyte commitment and terminal differentiation. However, the mechanisms by which EBF2 regulates chromatin to activate brown fat-specific genes in adipocytes were unknown. ChIP-seq (chromatin immunoprecipitation [ChIP] followed by deep sequencing) analyses in brown adipose tissue showed that EBF2 binds and regulates the activity of lineage-specific enhancers. Mechanistically, EBF2 physically interacts with the chromatin remodeler BRG1 and the BAF chromatin remodeling complex in brown adipocytes. We identified the histone reader protein DPF3 as a brown fat-selective component of the BAF complex that was required for brown fat gene programming and mitochondrial function. Loss of DPF3 in brown adipocytes reduced chromatin accessibility at EBF2-bound enhancers and led to a decrease in basal and catecholamine-stimulated expression of brown fat-selective genes. Notably, Dpf3 is a direct transcriptional target of EBF2 in brown adipocytes, thereby establishing a regulatory module through which EBF2 activates and also recruits DPF3-anchored BAF complexes to chromatin. Together, these results reveal a novel mechanism by which EBF2 cooperates with a tissue-specific chromatin remodeling complex to activate brown fat identity genes.

AB - The transcription factor early B-cell factor 2 (EBF2) is an essential mediator of brown adipocyte commitment and terminal differentiation. However, the mechanisms by which EBF2 regulates chromatin to activate brown fat-specific genes in adipocytes were unknown. ChIP-seq (chromatin immunoprecipitation [ChIP] followed by deep sequencing) analyses in brown adipose tissue showed that EBF2 binds and regulates the activity of lineage-specific enhancers. Mechanistically, EBF2 physically interacts with the chromatin remodeler BRG1 and the BAF chromatin remodeling complex in brown adipocytes. We identified the histone reader protein DPF3 as a brown fat-selective component of the BAF complex that was required for brown fat gene programming and mitochondrial function. Loss of DPF3 in brown adipocytes reduced chromatin accessibility at EBF2-bound enhancers and led to a decrease in basal and catecholamine-stimulated expression of brown fat-selective genes. Notably, Dpf3 is a direct transcriptional target of EBF2 in brown adipocytes, thereby establishing a regulatory module through which EBF2 activates and also recruits DPF3-anchored BAF complexes to chromatin. Together, these results reveal a novel mechanism by which EBF2 cooperates with a tissue-specific chromatin remodeling complex to activate brown fat identity genes.

KW - Adipogenesis/genetics

KW - Adipose Tissue, Brown/cytology

KW - Animals

KW - Basic Helix-Loop-Helix Transcription Factors/physiology

KW - Cell Lineage/genetics

KW - Cells, Cultured

KW - Chromatin/metabolism

KW - Chromatin Assembly and Disassembly

KW - Chromosomal Proteins, Non-Histone/metabolism

KW - DNA-Binding Proteins/genetics

KW - Gene Expression Regulation

KW - Histones/metabolism

KW - Mice

KW - Mice, Inbred C57BL

KW - Mice, Knockout

KW - Transcription Factors/genetics

KW - Transcription, Genetic

U2 - 10.1101/gad.294405.116

DO - 10.1101/gad.294405.116

M3 - Journal article

C2 - 28428261

SN - 0890-9369

VL - 31

SP - 660

EP - 673

JO - Genes & Development

JF - Genes & Development

IS - 7

ER -