Abstract
BackgroundBivalent chromatin domains consisting of the activating histone 3 lysine 4 trimethylation (H3K4me3) and repressive histone 3 lysine 27 trimethylation (H3K27me3) histone modifications are enriched at developmental genes that are repressed in embryonic stem cells but active during differentiation. However, it is unknown whether another repressive histone modification, histone 4 lysine 20 trimethylation (H4K20me3), co-localizes with activating histone marks in ES cells.ResultsHere, we describe the previously uncharacterized coupling of the repressive H4K20me3 heterochromatin mark with the activating histone modifications H3K4me3 and histone 3 lysine 36 trimethylation (H3K36me3), and transcriptional machinery (RNA polymerase II; RNAPII), in ES cells. These newly described bivalent domains consisting of H3K4me3/H4K20me3 are predominantly located in intergenic regions and near transcriptional start sites of active genes, while H3K36me3/H4K20me3 are located in intergenic regions and within gene body regions of active genes. Global sequential ChIP, also termed reChIP-Seq, confirmed the simultaneous presence of H3K4me3 and H4K20me3 at the same genomic regions in ES cells. Genes containing H3K4me3/H4K20me3 exhibit decreased RNAPII pausing and are poised for deactivation of RNAPII binding during differentiation relative to H3K4me3 marked genes. An evaluation of transcription factor (TF) binding motif enrichment revealed that DNA sequence may play a role in shaping the landscape of these novel bivalent domains. Moreover, H3K4me3/H4K20me3 and H3K36me3/H4K20me3 bound regions are enriched with repetitive LINE and LTR elements.ConclusionsOverall, these findings highlight a previously undescribed subnetwork of ES cell transcriptional circuitry that utilizes dual marking of the repressive H4K20me3 mark with activating histone modifications.
Highlights
Bivalent chromatin domains consisting of the activating histone 3 lysine 4 trimethylation (H3K4me3) and repressive histone 3 lysine 27 trimethylation (H3K27me3) histone modifications are enriched at developmental genes that are repressed in embryonic stem cells but active during differentiation
Bivalent domains have been identified in adult stem cells and lineage-committed preadipocytes, where Histone 3 (H3K4me3) was found to co-localize with the repressive Histone 3 (H3K9me3) histone modification at adipogenic master regulators [7]. While these results suggest that the histone 3, lysine 9 trimethylation (H3K9me3) heterochromatin mark pairs with the activating H3K4me3 mark in adult stem cells, it is unknown whether histone 4, lysine 20 trimethylation (H4K20me3), which is enriched at heterochromatin regions, co-localizes with H3K4me3 in Embryonic stem (ES) cells
Co-localization of H4K20me3 with H3K4me3 and RNA polymerase II (RNAPII) in ES cells To investigate whether H4K20me3 is enriched at genes with activating histone modifications in ES cells, we compared Chromatin immunoprecipitation (ChIP)-Seq regions occupied by H4K20me3 (GSE94086) [17] and H3K4me3 (GSE53093) [4], and H4K20me3 and RNAPII (GSE94739) [18], and found that 27% of H4K20me3 occupied regions contain H3K4me3 marks (Fig. 1a, top left), and 26% were bound by RNAPII (Fig. 1a, top right)
Summary
Bivalent chromatin domains consisting of the activating histone 3 lysine 4 trimethylation (H3K4me3) and repressive histone 3 lysine 27 trimethylation (H3K27me3) histone modifications are enriched at developmental genes that are repressed in embryonic stem cells but active during differentiation. It is unknown whether another repressive histone modification, histone 4 lysine 20 trimethylation (H4K20me3), co-localizes with activating histone marks in ES cells. 4 (H3K4), is thought to contribute to the regulation of ES cell self-renewal and pluripotency by regulating chromatin structure [1], marking active gene regulatory networks, and influencing the transcriptional state of the underlying DNA sequencing. Genes with H3K4me3/ H3K27me bivalent domains are thought to be poised for activation upon differentiation, where H3K27me marks silence developmental genes in ES cells, and H3K4me
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