HNF4A defines tissue-specific circadian rhythms by beaconing BMAL1::CLOCK chromatin binding and shaping the\xa0rhythmic chromatin landscape

Meng Qu,Steve A Kay,Han Qu,Zhenyu Jia

doi:10.1038/s41467-021-26567-3

Meng Qu, Steve A Kay + Show 2 more

Open Access

https://doi.org/10.1038/s41467-021-26567-3

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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.

Highlights

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 previously demonstrated that hepatocyte nuclear factor 4A (HNF4A) modulates peripheral circadian clocks in cell cultures[24]
Our results reveal a collaborative effort between HNF4A and the clock machinery in shaping tissue-specific chromatin landscape and circadian rhythms that are vital for liver biology

Summary

Introduction

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 (H3K4me[1] and H3K27ac). Expressing HNF4A remodels chromatin landscape and nucleates distinct tissue-specific BMAL1 chromatin binding events, predominantly in enhancer regions. 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. The core of the mammalian circadian clock, composed of two interlocked transcriptional feedback loops, relies on chromatin occupancy of the master transcription factor heterodimer BMAL1::CLOCK at the E-box DNA element. Genes that are required for particular tasks of a cell type display accessible chromatin structure allowing for the binding of necessary machinery to facilitate gene expression[11]. The pioneer TFs recruit histone methyltransferases MLL3/4 to deposit histone mark

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