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Cited by 26Peroxisome Proliferator-Activated ReceptorsAdipose Tissue and MetabolismGenomics and Chromatin Dynamics

MLL3/MLL4-Associated PAGR1 Regulates Adipogenesis by Controlling Induction of C/EBP β and C/EBP δ

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Lee, Ji-Eun, Cho, Young-Wook, Deng, Chu-Xia, Ge, Kai·2020·Molecular and Cellular Biology
DOI 10.1128/mcb.00209-20PMC PMC7431048
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Abstract

Transcription factors C/EBPβ and C/EBPδ are induced within hours after initiation of adipogenesis in culture. They directly promote the expression of master adipogenic transcription factors peroxisome proliferator-activated receptor γ (PPARγ) and C/EBPα and are required for adipogenesis in vivo. However, the mechanism that controls the induction of C/EBPβ and C/EBPδ remains elusive. We previously showed that histone methyltransferases MLL3/MLL4 and associated PTIP are required for the induction of PPARγ and C/EBPα during adipogenesis. Here, we show MLL3/MLL4/PTIP-associated protein PAGR1 (also known as PA1) cooperates with phosphorylated CREB and ligand-activated glucocorticoid receptor to directly control the induction of C/EBPβ and C/EBPδ in the early phase of adipogenesis. Deletion of Pagr1 in white and brown preadipocytes prevents the induction of C/EBPβ and C/EBPδ and leads to severe defects in adipogenesis. Adipogenesis defects in PAGR1-deficient cells can be rescued by the ectopic expression of C/EBPβ or PPARγ. Finally, the deletion of Pagr1 in Myf5+ precursor cells impairs brown adipose tissue and muscle development. Thus, by controlling the induction of C/EBPβ and C/EBPδ, PAGR1 plays a critical role in adipogenesis.

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  • MLL4 binding at enhancers coincides with the binding of master regulators.

    “MLL4 binding at enhancers has been shown to coincide with the binding of master regulators42–44.”

    From HNF4A guides the MLL4 complex to establish and maintain H3K4me1 at gene regulatory elements (2024) · cites this paper as [44]

    The Discussion says MLL3/MLL4 control induction of master adipogenic transcription factors, and the References list an earlier study on MLL4 and enhancer activation. Neither passage says that MLL4 binding at enhancers coincides with master-regulator binding; searches for MLL4 binding and enhancer co-occupancy found no such statement in our copy. (LLM, conf=0.72)

    Experimental — accuracy not yet measured

  • Some studies show that signalling-dependent and cell type-specific TFs are capable of recruiting MLL4 to establish H3K4me1 at enhancers.

    “While some studies show that signalling-dependent and cell type-specific TFs are capable of recruiting MLL4 to establish H3K4me1 at enhancers44–47, whether HNF4A has this function is not known.”

    From HNF4A guides the MLL4 complex to establish and maintain H3K4me1 at gene regulatory elements (2024) · cites this paper as [44]

    The Discussion describes MLL3/MLL4-associated PAGR1 regulating adipogenic transcription factors, and the Regulation of gene expression by PAGR1 section describes signal-activated CREB recruiting PAGR1 to a promoter. Neither passage says that transcription factors recruit MLL4 to enhancers to establish H3K4me1. Searches for H3K4me1, MLL4 recruitment, and enhancer methylation found no passage establishing that mechanism in our copy. (LLM, conf=0.72)

    Experimental — accuracy not yet measured

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Cited by

Sorted by citations

Authors
Lee, J.-E., Cho, Y.-W., Deng, C.-X., & Ge, K.
Affiliations
National Institutes of Health (US)
Corresponding author
Ge, Kai
ORCID
Venue
Molecular and Cellular Biology
Publisher
Informa UK Limited
Published
2020-08-14
Volume
40
Issue
17
ISSN
  • 0270-7306 (ISSN-L)
  • 1098-5549
DOI
10.1128/mcb.00209-20
PMC
PMC7431048
OpenAlex
W3037385521
Cited by
26
References
1
Citations by year
2026: 4 · 2025: 3 · 2024: 8 · 2023: 4 · 2022: 2 · 2021: 4 · 2020: 1
FWCI
0.89
Type
journal article
Language
en
Open access
Licence
Locations
  • Molecular and Cellular Biology (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
Funders
HHS | NIH | National Institute of Diabetes and Digestive and Kidney Diseases
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Peroxisome Proliferator-Activated Receptors
  • Health Sciences › Medicine › Physiology › Adipose Tissue and Metabolism
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
Keywords
adipogenesis, C/EBPβ, C/EBPδ, PTIP, histone methyltransferase, CREB phosphorylation, glucocorticoid receptor, PPARγ, C/EBPα, preadipocytes, brown adipose tissue, myogenesis, transcriptional regulation
MeSH terms
Histone Methyltransferases, Animals, Adipose Tissue, Brown, Cell Differentiation, DNA-Binding Proteins, Protein Binding, Histone-Lysine N-Methyltransferase, Adipocytes, Mice, Knockout, Cell Cycle Proteins, CCAAT-Enhancer-Binding Protein-beta, 3T3-L1 Cells, PPAR gamma, Adipogenesis, Mice, CCAAT-Enhancer-Binding Protein-delta

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