Genetic Control of Chromatin States in Humans Involves Local and Distal Chromosomal Interactions

Abstract

SUMMARY Deciphering the impact of genetic variants on gene regulation is fundamental to understanding human disease. Although gene regulation often involves long-range interactions, it is unknown to what extent non-coding genetic variants influence distal molecular phenotypes. Here, we integrate chromatin profiling for three histone marks in lymphoblastoid cell lines (LCLs) from 75 sequenced individuals with LCL-specific Hi-C and ChIA-PET-based chromatin contact maps to uncover one of the largest collections of local and distal histone quantitative trait loci (hQTLs). Distal QTLs are enriched within topologically associated domains and exhibit largely concordant variation of chromatin state coordinated by proximal and distal non-coding genetic variants. Histone QTLs are enriched for common variants associated with autoimmune diseases and enable identification of putative target genes of disease-associated variants from genome-wide association studies. These analyses provide insights into how genetic variation can affect human disease phenotypes by coordinated changes in chromatin at interacting regulatory elements.

The second decade of 3C technologies: detailed insights into nuclear organization

“…In line with this, gene silencing on the inactive X chromosome in female mammalian cells was shown to also occur at the level of TADs, and gene clusters of escapees that do not become silenced correlate with TADs (Marks et al 2015). Further strong evidence for TADs being the functional units of the genome came from two recent studies that established the existence of the long-range impact of genetic variation on histone modifications elsewhere on chromosomes: Both studies showed that such communication takes place in the context of TADs (Grubert et al 2015;Waszak et al 2015). TADs are formed during early G1 of the cell cycle, concomitant with the establishment of the replication timing program (Dileep et al 2015), and TAD boundaries often coincide with replication domain boundaries (Pope et al 2014).…”

Expression and regulation of C/EBPα in normal myelopoiesis and in malignant transformation

“…Genomewide association studies showed several events of single nucleotide variants (SNVs) occurring at enhancers of disease-causing genes. 114,115 Using the knowledge revealed so far about the role of SNVs or mutations in gene deregulation and disease susceptibility, it could be hypothesized that such alterations may be causative for low CEBPA expression in these CEBPA low AML subgroups. The application of DNA custom capture sequencing in large AML cohorts would be a potential tool to reveal mutations or SNVs that may be occurring in the CEBPA locus.…”

Recent advances in understanding nuclear size and shape

“…One of the most widely used methods to detect higherorder chromatin structure is the chromosome conformation capture (3C) family of techniques. 146,153,160 Chromatin immunoprecipitation sequencing (ChIP-seq), micrococcal nuclease sequencing (MNase-seq), and chromatin immunoprecipitation exonuclease (ChIP-exo) methodologies provide information over the »1-150 bp length scale, allowing for analysis of nucleosome fiber folding 149,[161][162][163][164] . While these types of approaches provide information on populations of cells, single-cell approaches have now become feasible.…”