Interdependence between histone marks and steps in Pol II transcription

Abstract

We trained a sensitive machine learning tool to infer the distribution of histone marks using maps of nascent transcription. Transcription captured the variation in active histone marks and complex chromatin states, like bivalent promoters, down to single-nucleosome resolution and at an accuracy that rivaled the correspondence between independent ChIP-seq experiments. The relationship between active histone marks and transcription was conserved in all cell types examined, allowing individual labs to annotate active functional elements in mammals with similar richness as major consortia. Using imputation as an interpretative tool uncovered cell-type specific differences in how the PRC2-dependent repressive mark, H3K27me3, corresponds to transcription, and revealed that transcription initiation requires both chromatin accessibility and an active chromatin environment demonstrating that initiation is less promiscuous than previously thought.

Enhancer RNAs predict enhancer–gene regulatory links and are critical for enhancer function in neuronal systems

“…While genome-wide enhancer identification traditionally relies on extensive ChIP-seq, ATAC-seq, and/or HiC-seq datasets to asses location and activity states, our findings are in line with recent work by Wang et al. and emphasize the advantages of transcriptional information as an indicator of local chromatin states ( 77 ). In this study, the authors developed a machine learning tool to predict chromatin landscapes with nucleosome resolution based exclusively on nascent transcription.…”

Efficient chromatin accessibility mapping in situ by nucleosome-tethered tagmentation

“…Therefore, our demonstration that Tn5 tethered to H3K4me2 or H3K4me3 histone tail residues efficiently tagments accessible sites, implies that accessibility at regulatory elements is created by events immediately following transcription initiation. This mechanistic interpretation is supported by the mapping of CUTAC sites just upstream of RNAPII, and is consistent with the recent demonstration that PRO-seq data can be used to accurately impute "active" histone modifications (16). Thus CUTAC identifies active promoters and enhancers that produce enhancer RNAs, which might help explain why ~95% of ATAC-seq peaks are detected by CUTAC and vice-versa ( Figure 4B-C).…”

“…The rationale for this mapping strategy is that the enzymes that modify histone tails and the chaperones that deposit nucleosome subunits are most active close to the sites of initiation of transcription, which typically occurs bidirectionally at both gene promoters and enhancers to produce stable mRNAs and unstable enhancer RNAs. Although the marks left behind by active transcriptional initiation ‘point back’ to the NDR, this cause-effect connection between the NDR and the histone marks is only by inference ( Wang et al, 2020 ), and direct evidence is lacking that a histone mark is associated with an NDR.…”

Efficient chromatin accessibility mappingin situby nucleosome-tethered tagmentation

“…Therefore, our demonstration that Tn5 tethered to H3K4me2 or H3K4me3 histone tail residues efficiently tagments accessible sites, implies that accessibility at regulatory elements is created by events immediately following transcription initiation. This mechanistic interpretation is supported by the mapping of CUTAC sites just upstream of RNAPII, and is consistent with the recent demonstration that PRO-seq data can be used to accurately impute "active" histone modifications (16). Thus CUTAC identifies active promoters and enhancers that produce enhancer RNAs, which might help explain why ~95% of ATAC-seq peaks are detected by CUTAC and vice-versa ( Figure 5B-C).…”

“…The rationale for this mapping strategy is that the enzymes that modify histone tails and the chaperones that deposit nucleosome subunits are most active close to the sites of initiation of transcription, which typically occurs bidirectionally at both gene promoters and enhancers to produce stable mRNAs and unstable enhancer RNAs. Although the marks left behind by active transcriptional initiation "point back" to the NDR, this cause-effect connection between the NDR and the histone marks is only by inference (16), and direct evidence is lacking that a histone mark is associated with an NDR.…”