Divergent wiring of repressive and active chromatin interactions between mouse embryonic and trophoblast lineages

Abstract

The establishment of the embryonic and trophoblast lineages is a developmental decision underpinned by dramatic differences in the epigenetic landscape of the two compartments. However, it remains unknown how epigenetic information and transcription factor networks map to the 3D arrangement of the genome, which in turn may mediate transcriptional divergence between the two cell lineages. Here, we perform promoter capture Hi-C experiments in mouse trophoblast (TSC) and embryonic (ESC) stem cells to understand how chromatin conformation relates to cell-specific transcriptional programmes. We find that key TSC genes that are kept repressed in ESCs exhibit interactions between H3K27me3-marked regions in ESCs that depend on Polycomb repressive complex 1. Interactions that are prominent in TSCs are enriched for enhancer–gene contacts involving key TSC transcription factors, as well as TET1, which helps to maintain the expression of TSC-relevant genes. Our work shows that the first developmental cell fate decision results in distinct chromatin conformation patterns establishing lineage-specific contexts involving both repressive and active interactions.

Organization of the Pluripotent Genome

“…Strikingly, these experiments revealed that following reprogramming, ESC-specific contacts became more frequent at genes related to developmental processes, the formation of which preceded changes in transcription (Stadhouders et al 2018). In support of this finding, another study, using a technique called promoter capture Hi-C, found that developmental pathway-related genes are enriched in ESC-specific promoterenhancer interactions; a large amount of distinct cell-type-specific contacts were detected for both ESCs and fetal liver cells at promoters interacting with more than 10 enhancers (Schoenfelder et al 2018).…”

Defective folate metabolism causes germline epigenetic instability and distinguishesHiraas a phenotype inheritance biomarker

“…5a-b). To understand the DMR epigenetic signature in a developmental context, published ChIP-seq data sets in spermatozoa 37 , and wildtype embryonic stem cell (ESC) 42,43 and trophoblast stem cell (TSC) [44][45][46] lines were assessed. In TSCs, histone marks at all three DMRs were largely absent ( Fig.…”

“…Epigenetic signature of the intragenic Cwc27 DMR in wildtype ESCs, TSCs and spermatozoa. Enrichment of DNA binding proteins (TET1, CTCF, PRM1, H3) and histone modifications (H3K27ac, H3K27me3, H3K4me1, H3K4me3, H3K9me3) in the Cwc27 locus on Chr13 (~37,000 kb downstream of Mtrr gene) using published ChIP-seq data sets in wildtype embryonic stem cells (ESCs), trophoblast stem cells (TSCs) 42 , and spermatozoa (Sp) 37 . Tn5 transposase sensitive sites (THSS) were also determined using published ATAC-seq data sets of normal B6D2F1 mouse epiblast and extraembryonic ectoderm (ExE) at embryonic day 6.5 38 or normal CD1 spermatozoa 37 .…”

“…Failure of cardiac development, pericardial edema, abnormal neural tube morphology, embryo growth restriction, lethality by E10.5 51 Male infertility, pre-weaning lethality, abnormal blood homeostasis, postnatal growth restriction, retinal degeneration (IMPC database*) Neonatal lethality likely due to respiratory distress, impaired uretic smooth muscle 82 n/a n/a n/a Embryonic abnormalities (e.g., heart defects and neural tube defects), gastrulation incomplete, embryonic lethality before E10.5 83 Anterior-posterior cerebellar patterning defects, Cwc27 processed *The source given in the table is the link for the raw fastq files, which was reused by ref 42 . We used the processed file provided by the authors of ref 42 . ESC, embryonic stem cells; ExE, extraembryonic ectoderm; Sperm, spermatozoa; TSC, trophoblast stem cells…”

Functional evaluation of transposable elements as transcriptional enhancers in mouse embryonic and trophoblast stem cells

“…This disregards 3D genome conformation, which enables long-range interactions and is not restricted to one-to-one relationships between TEs and genes. We therefore coupled TE+ enhancers to genes they putatively regulate based on promoter capture Hi-C (PCHi-C) data that we recently generated in ESCs and TSCs (Schoenfelder et al 2018). Only 34-44% of TE+ enhancers interacted with at least one gene promoter, which was nonetheless higher than the proportion of non-enhancer TEs with gene promoter interactions (21-28%, Supplementary Figure 4A).…”