Abstract
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.
Highlights
Cell type-specific enhancers are activated by coordinated actions of lineage-determining transcription factors (LDTFs) and chromatin regulators
Given that MLL4 is important for enhancer activation, cell differentiation and cell type-specific gene expression, we investigated the relationship between BRM-associated factor (BAF) and MLL4 before and during adipogenesis, revealing that BAF and MLL4 colocalize with LDTFs on active enhancers and facilitate enhancer activation in an interdependent manner
By motif analysis of the top 3,000 binding sites of each subunit, we found that SMARCA4, SS18 and ARID1A binding regions were enriched with motifs of AP-1 family TFs Jdp[2], JunD and Jun in preadipocytes (D-3), but with motifs of adipogenic TFs such as C/EBPα, C/EBPβ, and ATF4 during adipogenesis (D2)
Summary
Cell type-specific enhancers are activated by coordinated actions of lineage-determining transcription factors (LDTFs) and chromatin regulators. 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. Throughout development, chromatin architecture undergoes dynamic changes that are critical for promoting appropriate cell type-specific enhancer activation and gene expression. These changes are coordinated by the action of transcription factors (TFs) and epigenomic regulators, including. The recently characterized GBAF is a smaller complex containing SMARCA4 or SMARCA2, the initial core, SS18, and GBAF-specific subunits GLTSCR1/L and BRD95–7 These three distinct complexes exhibit different genomic localization patterns. PBAF is more localized on promoter regions, and GBAF binding sites are enriched with the CTCF motif[11,12]
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
