Abstract
BackgroundPluripotency of embryonic stem (ES) cells is controlled in part by chromatin-modifying factors that regulate histone H3 lysine 4 (H3K4) methylation. However, it remains unclear how H3K4 demethylation contributes to ES cell function.ResultsHere, we show that KDM5B, which demethylates lysine 4 of histone H3, co-localizes with H3K4me3 near promoters and enhancers of active genes in ES cells; its depletion leads to spreading of H3K4 methylation into gene bodies and enhancer shores, indicating that KDM5B functions to focus H3K4 methylation at promoters and enhancers. Spreading of H3K4 methylation to gene bodies and enhancer shores is linked to defects in gene expression programs and enhancer activity, respectively, during self-renewal and differentiation of KDM5B-depleted ES cells. KDM5B critically regulates H3K4 methylation at bivalent genes during differentiation in the absence of LIF or Oct4. We also show that KDM5B and LSD1, another H3K4 demethylase, co-regulate H3K4 methylation at active promoters but they retain distinct roles in demethylating gene body regions and bivalent genes.ConclusionsOur results provide global and functional insight into the role of KDM5B in regulating H3K4 methylation marks near promoters, gene bodies, and enhancers in ES cells and during differentiation.
Highlights
Pluripotency of embryonic stem (ES) cells is controlled in part by chromatin-modifying factors that regulate histone H3 lysine 4 (H3K4) methylation
Our results revealed that KDM5B binds to promoters, enhancers, and gene body regions of active genes as assessed by average profiles of KDM5B binding at transcriptional start and end sites (TSS-TES) of active genes (Figure 1A, red line, highest 25% expressed) and inactive genes (Figure 1A, green line, lowest 25% expressed)
A comparison of average KDM5B binding and H3K4me3 marks around transcriptional start site (TSS) showed that KDM5B binds further downstream into gene body regions compared with the distribution of H3K4me3 marks (Figure 1B)
Summary
Pluripotency of embryonic stem (ES) cells is controlled in part by chromatin-modifying factors that regulate histone H3 lysine 4 (H3K4) methylation. It remains unclear how H3K4 demethylation contributes to ES cell function. ES cells express networks of TFs, such as Oct, Sox, Nanog, and Tbx that regulate self-renewal and differentiation by occupying promoters and enhancers to activate gene expression of ES cellenriched genes and to repress developmental genes [1,2,3]. Posttranslational modification of histone tails impacts the activity of epigenetic modifiers and the transcriptional state (active or inactive) of the underlying chromatin, which is important for controlling expression of networks of genes that promote self-renewal or differentiation
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