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Cited by 65Circadian rhythm and melatoninGenomics and Chromatin DynamicsPlant Molecular Biology Research

HNF4A defines tissue-specific circadian rhythms by beaconing BMAL1::CLOCK chromatin binding and shaping the rhythmic chromatin landscape

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Qu, Meng, Qu, Han, Jia, Zhenyu, Kay, Steve A.·2021·Nature Communications
DOI 10.1038/s41467-021-26567-3PMC PMC8566521
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Abstract

Transcription modulated by the circadian clock is diverse across cell types, underlying circadian control of peripheral metabolism and its observed perturbation in human diseases. We report that knockout of the lineage-specifying Hnf4a gene in mouse liver causes associated reductions in the genome-wide distribution of core clock component BMAL1 and accessible chromatin marks (H3K4me1 and H3K27ac). Ectopically expressing HNF4A remodels chromatin landscape and nucleates distinct tissue-specific BMAL1 chromatin binding events, predominantly in enhancer regions. Circadian rhythms are disturbed in Hnf4a knockout liver and HNF4A-MODY diabetic model cells. Additionally, the epigenetic state and accessibility of the liver genome dynamically change throughout the day, synchronized with chromatin occupancy of HNF4A and clustered expression of circadian outputs. Lastly, Bmal1 knockout attenuates HNF4A genome-wide binding in the liver, likely due to downregulated Hnf4a transcription. Our results may provide a general mechanism for establishing circadian rhythm heterogeneity during development and disease progression, governed by chromatin structure.

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  • HNF4A bound regions (HBRs) are flanked by nucleosomes marked with H3K4me1.

    “HNF4A bound regions (HBRs) are flanked by nucleosomes marked with H3K4me148–50, leading us to question whether HNF4A contributes to the establishment and maintenance of H3K4me1 at HBRs.”

    From HNF4A guides the MLL4 complex to establish and maintain H3K4me1 at gene regulatory elements (2024) · cites this paper as [50]

    The Results section on Hnf4a knockout reports H3K4me1 at HNF4A-binding sites and reduced H3K4me1 there after knockout. The paper does not establish the more specific claim that HNF4A-bound regions are flanked by H3K4me1-marked nucleosomes. Page numbers are not available in our copy. (LLM, conf=0.84)

    Experimental — accuracy not yet measured

  • HNF4A depletion in adult mouse liver reduces H3K4me1 at locations normally occupied by HNF4A.

    “In agreement with recent papers50,53, we observed reduced levels of H3K4me1 in cKO livers at locations normally occupied by HNF4A (Fig. 1b).”

    From HNF4A guides the MLL4 complex to establish and maintain H3K4me1 at gene regulatory elements (2024) · cites this paper as [50]

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Cited by

Sorted by citations

Authors
Qu, M., Qu, H., Jia, Z., & Kay, S. A.
Affiliations
  • University of Southern California (US)
  • University of California, Riverside (US)
Corresponding author
  • Qu, Meng
  • Kay, Steve A.
ORCID
Venue
Nature Communications
Publisher
Springer Science and Business Media LLC
Published
2021-11-03
Volume
12
Issue
1
Pages
6350-6350
ISSN
2041-1723 (ISSN-L)
DOI
10.1038/s41467-021-26567-3
PMC
PMC8566521
OpenAlex
W3210312599
Cited by
65
References
6
Citations by year
2026: 5 · 2025: 13 · 2024: 13 · 2023: 23 · 2022: 11
FWCI
6.16
Type
journal article
Language
en
Open access
Licence
Locations
  • Nature Communications (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • RePEc: Research Papers in Economics (submittedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
U.S. Department of Health & Human Services | NIH | National Institute of Diabetes and Digestive and Kidney Diseases (5R01DK108087)
Topics
  • Life Sciences › Neuroscience › Endocrine and Autonomic Systems › Circadian rhythm and melatonin
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
  • Life Sciences › Agricultural and Biological Sciences › Plant Science › Plant Molecular Biology Research
Keywords
HNF4α, circadian clock, Bmal1, clocks, chromatin accessibility, H3K4me1, H3K27ac, enhancers, liver, maturity-onset diabetes of the young, epigenetic regulation, chromatin binding
MeSH terms
Animals, Chromatin, Circadian Rhythm, DNA-Binding Proteins, Gene Expression Regulation, Histones, Humans, Liver, Male, Mutation, Genome, Mice, Knockout, Mice, Hepatocyte Nuclear Factor 4, CLOCK Proteins, ARNTL Transcription Factors, Epigenomics, Circadian Clocks

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