Annotation of Chromatin States in 66 Complete Mouse Epigenomes During Development

Abstract

The morphologically and functionally distinct cell types of a multicellular organism are maintained by epigenomes and gene expression programs. Phase III of the ENCODE Project profiled 66 mouse epigenomes across twelve tissues at daily intervals from embryonic day 10.5 to birth. Applying the ChromHMM algorithm to these epigenomes, we annotated eighteen chromatin states with characteristics of promoters, enhancers, transcribed regions, repressed regions, and quiescent regions throughout the developmental time course. Our integrative analyses delineate the tissue specificity and developmental trajectory of the loci in these chromatin states. Approximately 0.3% of each epigenome is assigned to a bivalent chromatin state, which harbors both active marks and the repressive mark H3K27me3. Highly evolutionarily conserved, these loci are enriched in silencers bound by Polycomb Repressive Complex proteins and the transcription start sites of their silenced target genes. This collection of chromatin state assignments provides a useful resource for studying mammalian development.

Placenta and fetal brain share a neurodevelopmental disorder DNA methylation profile in a mouse model of prenatal PCB exposure

“…Placental PCB DMRs differed from those in brain in that they were also enriched within promoters. Finally, PCB DMRs were tested for enrichment within an 18-chromatin-state model of mouse embryonic development, specifically forebrain tissue ( Data S2 ; van der Velde et al, 2021 ). PCB DMRs from all pairwise comparisons were significantly (q < 0.05) enriched within transcription start site (TSS) regions marked by active and bivalent chromatin during at least one developmental time point, and bivalent TSS was the top enrichment (odds ratio >2.4; q < 0.003) overall ( Figure 3C ).…”

“…This is evidenced by the top chromatin state enrichment: bivalent TSS. Although all chromatin states are highly conserved between human and mouse, the bivalent TSS chromatin state, which represents 1.2% of the entire genome across all tissues and ~0.3% in a specific tissue, is substantially more evolutionarily conserved than the other 17 chromatin states ( van der Velde et al, 2021 ). There are ~3,000 bivalent genes in each fetal tissue, which are poised for either activation and repression, and many of them are lineage-specific transcription factors that are repressed in the tissue assayed but expressed in others ( Ngan et al, 2020 ; van der Velde et al, 2021 ).…”

“…Although all chromatin states are highly conserved between human and mouse, the bivalent TSS chromatin state, which represents 1.2% of the entire genome across all tissues and ~0.3% in a specific tissue, is substantially more evolutionarily conserved than the other 17 chromatin states ( van der Velde et al, 2021 ). There are ~3,000 bivalent genes in each fetal tissue, which are poised for either activation and repression, and many of them are lineage-specific transcription factors that are repressed in the tissue assayed but expressed in others ( Ngan et al, 2020 ; van der Velde et al, 2021 ). Given the tissue-specific nature of the identified bivalent chromatin state, future research into the effects of PCB exposure on DNA methylation profiles in placenta and brain would benefit from examining specific regions and cell populations through sorting or single-cell sequencing.…”

DNA Methylation Dynamics and Dysregulation Delineated by High-Throughput Profiling in the Mouse

“…Because design intent categories can yield probes associated with more than one such category, we also characterized the final MM285 array content by mapping each probe to one of several non-overlapping consensus chromatin states (Figure 1C). We derived consensus chromatin states from 66 ENCODE chromHMM calls (van der Velde et al, 2021). Normalization of the probe coverage by the number of genomic CpGs in different chromatin states indicates that enhancers are the most overrepresented on the MM285 array, followed by promoters, and that quiescent chromatin regions are relatively underrepresented on the array, underscoring the utility of the array in characterizing gene transcription control (Figure 1C, S2B).…”

Multi-omics analysis reveals a crucial role for Retinoic Acid in promoting epigenetic and transcriptional competence of anin vitromodel of human Pharyngeal Endoderm

“…We selected a 10-state model as the one which better and more concisely describes the meaningful combinations between the HMs under investigation ( Figure 5A ); the human genome was segmented into 200 bp bins and each of such intervals was annotated with the states found in DE and PE. Based on the function that is commonly associated to known HM combinations (van der Velde et al, 2021) and on their overlap with annotated functional regions ( Figure 5B ), we renamed the model states to: TssA (active/acetylated Promoter), Tss (Promoter), TssFlnk (Tss flanking region), TssBiv (bivalent promoter), ReprPC (Polycomb-repressed), EnhA (active/acetylated enhancer), EnhPr (primed enhancer), EnhBiv (bivalent enhancer), Quies1 and Quies2 (quiescent regions with no histone marks, fused into Quies state in subsequent analyses). Looking at how the genomic distribution of functional chromatin states changes in the transition from DE to PE, we observed a clear decrease in the number of genomic regions repressed by Polycomb and occupied by active enhancers, and an increase in primed enhancer occupancy ( Figure S5D ).…”