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Cited by 191Genomics and Chromatin DynamicsEpigenetics and DNA MethylationAdipose Tissue and Metabolism

MLL3/MLL4 are required for CBP/p300 binding on enhancers and super-enhancer formation in brown adipogenesis

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Lai, Binbin, Lee, Ji-Eun, Jang, Younghoon, Wang, Lifeng, Peng, Weiqun, Ge, Kai·2017·Nucleic Acids Research
DOI 10.1093/nar/gkx234PMC PMC5499743
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Abstract

Histone H3K4me1/2 methyltransferases MLL3/MLL4 and H3K27 acetyltransferases CBP/p300 are major enhancer epigenomic writers. To understand how these epigenomic writers orchestrate enhancer landscapes in cell differentiation, we have profiled genomic binding of MLL4, CBP, lineage-determining transcription factors (EBF2, C/EBPβ, C/EBPα, PPARγ), coactivator MED1, RNA polymerase II, as well as epigenome (H3K4me1/2/3, H3K9me2, H3K27me3, H3K36me3, H3K27ac), transcriptome and chromatin opening during adipogenesis of immortalized preadipocytes derived from mouse brown adipose tissue (BAT). We show that MLL4 and CBP drive the dynamic enhancer epigenome, which correlates with the dynamic transcriptome. MLL3/MLL4 are required for CBP/p300 binding on enhancers activated during adipogenesis. Further, MLL4 and CBP identify super-enhancers (SEs) of adipogenesis and that MLL3/MLL4 are required for SE formation. Finally, in brown adipocytes differentiated in culture, MLL4 identifies primed SEs of genes fully activated in BAT such as Ucp1. Comparison of MLL4-defined SEs in brown and white adipogenesis identifies brown-specific SE-associated genes that could be involved in BAT functions. These results establish MLL3/MLL4 and CBP/p300 as master enhancer epigenomic writers and suggest that enhancer-priming by MLL3/MLL4 followed by enhancer-activation by CBP/p300 sequentially shape dynamic enhancer landscapes during cell differentiation. Our data also provide a rich resource for understanding epigenomic regulation of brown adipogenesis.

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  • Recent studies showed that the MLL4 complex recruits and activates p300 activity, involving UTX, at enhancers, resulting not only in methylation at H3K4 but also acetylation on H3K27 at target chromatin.

    “recent studies showed that the MLL4 complex recruits and activates p300 activity, involving UTX, at enhancers, resulting not only in methylation at H3K4 but also acetylation on H3K27 at target chromatin41,61.”

    From HNF4A guides the MLL4 complex to establish and maintain H3K4me1 at gene regulatory elements (2024) · cites this paper as [61]

    The Discussion (page unavailable) says MLL3/MLL4 facilitate CBP/p300 binding at enhancers and links the proteins to H3K4 methylation and H3K27 acetylation. The Results (Figure 5F; page unavailable) show that MLL4 interacts with UTX, but the paper does not establish that UTX mediates CBP/p300 recruitment or that the MLL4 complex activates p300 enzymatic activity. The Discussion says the binding mechanism remains unknown. (LLM, conf=0.88)

    Experimental — accuracy not yet measured

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Authors
Lai, B., Lee, J.-E., Jang, Y., Wang, L., Peng, W., & Ge, K.
Affiliations
  • National Institutes of Health (US)
  • George Washington University (US)
Corresponding author
  • Lai, Binbin
  • Lee, Ji-Eun
  • Peng, Weiqun
  • Ge, Kai
ORCID
Venue
Nucleic Acids Research
Publisher
Oxford University Press (OUP)
Published
2017-04-08
Volume
45
Issue
11
Pages
6388-6403
ISSN
  • 0305-1048 (ISSN-L)
  • 1362-4962
DOI
10.1093/nar/gkx234
PMC
PMC5499743
OpenAlex
W2604847558
Cited by
191
References
7
Citations by year
2026: 17 · 2025: 19 · 2024: 22 · 2023: 24 · 2022: 22 · 2021: 22 · 2020: 27 · 2019: 14 · 2018: 21 · 2017: 3
FWCI
7.26
Type
journal article
Language
en
Open access
Licence
public-domain
Locations
  • Nucleic Acids Research (publishedVersion, public-domain)
  • Europe PMC (PubMed Central) (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
Funders
  • National Institute of Allergy and Infectious Diseases (R21AI113806)
  • National Institute of Diabetes and Digestive and Kidney Diseases
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Epigenetics and DNA Methylation
  • Health Sciences › Medicine › Physiology › Adipose Tissue and Metabolism
Keywords
CBP/p300, super-enhancers, brown adipogenesis, H3K4 methylation, H3K27 acetylation, MED1, transcriptional coactivator, UCP1, preadipocytes, chromatin opening, cell differentiation
MeSH terms
Animals, Adipose Tissue, Brown, Cells, Cultured, DNA-Binding Proteins, Enhancer Elements, Genetic, Mice, Transgenic, Protein Binding, Histone-Lysine N-Methyltransferase, Transcriptional Activation, Adipogenesis, E1A-Associated p300 Protein, CREB-Binding Protein, Adipocytes, Brown, Transcriptome

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