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

Author

Listed:
  • Young-Kwon Park

    (Adipocyte Biology and Gene Regulation Section, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health (NIH))

  • Ji-Eun Lee

    (Adipocyte Biology and Gene Regulation Section, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health (NIH))

  • Zhijiang Yan

    (Laboratory of Genetics and Genomics, National Institute on Aging, NIH
    Wenzhou Medical University)

  • Kaitlin McKernan

    (Adipocyte Biology and Gene Regulation Section, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health (NIH))

  • Tommy O’Haren

    (Adipocyte Biology and Gene Regulation Section, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health (NIH))

  • Weidong Wang

    (Laboratory of Genetics and Genomics, National Institute on Aging, NIH)

  • Weiqun Peng

    (The George Washington University)

  • Kai Ge

    (Adipocyte Biology and Gene Regulation Section, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health (NIH))

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.

Suggested Citation

  • Young-Kwon Park & Ji-Eun Lee & Zhijiang Yan & Kaitlin McKernan & Tommy O’Haren & Weidong Wang & Weiqun Peng & Kai Ge, 2021. "Interplay of BAF and MLL4 promotes cell type-specific enhancer activation," Nature Communications, Nature, vol. 12(1), pages 1-16, December.
    • Handle: RePEc:nat:natcom:v:12:y:2021:i:1:d:10.1038_s41467-021-21893-y
    DOI: 10.1038/s41467-021-21893-y
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    Cited by:

    1. Dhurjhoti Saha & Solomon Hailu & Arjan Hada & Junwoo Lee & Jie Luo & Jeff A. Ranish & Yuan-chi Lin & Kyle Feola & Jim Persinger & Abhinav Jain & Bin Liu & Yue Lu & Payel Sen & Blaine Bartholomew, 2023. "The AT-hook is an evolutionarily conserved auto-regulatory domain of SWI/SNF required for cell lineage priming," Nature Communications, Nature, vol. 14(1), pages 1-17, December.

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