Interplay of BAF and MLL4 promotes cell type-specific enhancer activation

• Published in: Nature communications 2021-03, Vol.12 (1), p.1630-1630, Article 1630
• Main Authors: Park, Young-Kwon, Lee, Ji-Eun, Yan, Zhijiang, McKernan, Kaitlin, O’Haren, Tommy, Wang, Weidong, Peng, Weiqun, Ge, Kai
• Format: Article
• Language: English
• Subjects: 13/106; 13/51; 38/15; 38/90; 38/91; 631/208/135; 631/208/176; 631/208/199; 631/208/200; 631/80; 64/60; 82/1; 82/58; Adipogenesis; Adipogenesis - genetics; Animals; BRG1 protein; Cell activation; Cell Differentiation; Chromatin; Chromatin Assembly and Disassembly; Chromatin remodeling; Differentiation (biology); DNA Helicases; DNA-Binding Proteins - genetics; DNA-Binding Proteins - metabolism; Enhancer Elements, Genetic; Enhancers; Gene Expression Regulation; Histone methyltransferase; Histone-Lysine N-Methyltransferase - genetics; Histone-Lysine N-Methyltransferase - metabolism; Histones; Histones - metabolism; Humanities and Social Sciences; Kinases; Methyltransferase; Mice; multidisciplinary; Nuclear Proteins; Positive feedback; Promoter Regions, Genetic; Regulators; Science; Science (multidisciplinary); SMARCB1 Protein; SWI/SNF complex; Transcription activation; Transcription Factors
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-021-21893-y

Cell type-specific enhancers are activated by coordinated actions of lineage-determining transcription factors (LDTFs) and chromatin regulators. The SWI/SNF chromatin remodeling complex BAF and the histone H3K4 methyltransferase MLL4 (KMT2D) are both implicated in enhancer activation. However, the interplay between BAF and MLL4 in enhancer activation remains unclear. Using adipogenesis as a model system, we identify BAF as the major SWI/SNF complex that colocalizes with MLL4 and LDTFs on active enhancers and is required for cell differentiation. In contrast, the promoter enriched SWI/SNF complex PBAF is dispensable for adipogenesis. By depleting BAF subunits SMARCA4 (BRG1) and SMARCB1 (SNF5) as well as MLL4 in cells, we show that BAF and MLL4 reciprocally regulate each other’s binding on active enhancers before and during adipogenesis. By focusing on enhancer activation by the adipogenic pioneer transcription factor C/EBPβ without inducing cell differentiation, we provide direct evidence for an interdependent relationship between BAF and MLL4 in activating cell type-specific enhancers. Together, these findings reveal a positive feedback between BAF and MLL4 in promoting LDTF-dependent activation of cell type-specific enhancers. The SWI/SNF complex BAF and the histone H3K4 methyltransferase MLL4 (KMT2D) play critical roles in enhancer activation, however the interplay between them has remained unclear. Here the authors show that BAF and MLL4 are interdependent in promoting enhancer activation by lineage-determining transcription factors during adipogenesis.