Hepatocyte nuclear factor 4A (HNF4A/NR2a1), a transcriptional regulator of hepatocyte identity, controls genes that are crucial for liver functions, primarily through binding to enhancers. In mammalian cells, active and primed enhancers are marked by monomethylation of histone 3 (H3) at lysine 4 (K4) (H3K4me1) in a cell type-specific manner. How this modification is established and maintained at enhancers in connection with transcription factors (TFs) remains unknown. Using analysis of genome-wide histone modifications, TF binding, chromatin accessibility and gene expression, we show that HNF4A is essential for an active chromatin state. Using HNF4A loss and gain of function experiments in vivo and in cell lines in vitro, we show that HNF4A affects H3K4me1, H3K27ac and chromatin accessibility, highlighting its contribution to the establishment and maintenance of a transcriptionally permissive epigenetic state. Mechanistically, HNF4A interacts with the mixed-lineage leukaemia 4 (MLL4) complex facilitating recruitment to HNF4A-bound regions. Our findings indicate that HNF4A enriches H3K4me1, H3K27ac and establishes chromatin opening at transcriptional regulatory regions.
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| http://dx.doi.org/10.1038/s42003-024-05835-0 | DOI Listing |
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Article Synopsis
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- The PHD2 and PHD3 fingers of MLL4 and MLL3 interact with ASXL2, a component of the PR-DUB complex, which plays a role in regulating histone modifications.
- Analysis shows that the MLL3/4 and PR-DUB complexes work together in a way that relies on the binding of ASXL1/2, which is essential for recruiting the deubiquitinase BAP1 to active enhancers in embryonic stem cells.
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