The pluripotent regulatory circuitry connecting promoters to their long-range interacting elements

Abstract

The mammalian genome harbors up to one million regulatory elements often located at great distances from their target genes. Long-range elements control genes through physical contact with promoters and can be recognized by the presence of specific histone modifications and transcription factor binding. Linking regulatory elements to specific promoters genome-wide is currently impeded by the limited resolution of high-throughput chromatin interaction assays. Here we apply a sequence capture approach to enrich Hi-C libraries for >22,000 annotated mouse promoters to identify statistically significant, long-range interactions at restriction fragment resolution, assigning long-range interacting elements to their target genes genome-wide in embryonic stem cells and fetal liver cells. The distal sites contacting active genes are enriched in active histone modifications and transcription factor occupancy, whereas inactive genes contact distal sites with repressive histone marks, demonstrating the regulatory potential of the distal elements identified. Furthermore, we find that coregulated genes cluster nonrandomly in spatial interaction networks correlated with their biological function and expression level. Interestingly, we find the strongest gene clustering in ES cells between transcription factor genes that control key developmental processes in embryogenesis. The results provide the first genome-wide catalog linking gene promoters to their longrange interacting elements and highlight the complex spatial regulatory circuitry controlling mammalian gene expression.

Enhancer-gene maps in the human and zebrafish genomes using evolutionary linkage conservation

“…Methods that have been developed to address this problem fall in three broad categories. The first uses 35 chromosomal conformation capture techniques to identify physical interaction between two loci in the genome [25][26][27][28][29][30] , but it is not clear which of these interactions are linked to a regulatory role. The second measures the correlation of transcription activity between noncoding sequences and nearby genes 31,32 , assuming the two are signatures of a coordinated regulatory function.…”

Chromosome conformation capture technologies and their impact in understanding genome function

“…Most of these assays are based on hybridization of sequencing adaptor-ligated 3C (Capture C) and Hi-C samples (CHi-C and HiCap) respectively, followed by pull-down using biotinylated RNA molecules (120 nucleotides). In terms of detecting genuine chromosomal interactions, CHi-C and HiCap performed better than Capture C did, which has been suggested to depend on more effective capture of the genuine interactions in the Hi-C method over regular 3C (Sahlen et al 2015;Schoenfelder et al 2015). Sahlen et al has further shown that Capture C-enriched fragments are strongly enriched for unligated fragments (>1 kb apart) (Sahlen et al 2015).…”

“…A number of such modifications have been published (Fig. 3b), called Capture C, Capture Hi-C (CHi-C), HiCap, and targeted chromatin capture (T2C) (Dryden et al 2014;Hughes et al 2014;Jager et al 2015;Kolovos et al 2014;Mifsud et al 2015;Sahlen et al 2015;Schoenfelder et al 2015). Most of these assays are based on hybridization of sequencing adaptor-ligated 3C (Capture C) and Hi-C samples (CHi-C and HiCap) respectively, followed by pull-down using biotinylated RNA molecules (120 nucleotides).…”

Toward Integrative Annotation of Cell Type-Specific Epigenomes to Better Understand Human Biology and Disease

“…It was estimated that over one million regulatory elements are in the mammalian genome for supporting distant enhancer-promoter interactions in a cell-or tissue-specific manner [10,11] Editorial Bayarsaihan topology and its role in gene expression [12]. In mouse ESCs and fetal liver cells, active interacting elements are enriched in active histone modification marks with higher TF occupancy, whereas nonactive distal regulatory elements are marked with repressive histone modifications.…”

“…Furthermore, nonrandom clustering of genes that are coregulated in spatial nuclear space correlates with their expression and biological role. In ESCs, the strongest clustering occurs between genes encoding TFs that control key developmental processes [12]. Therefore, higher-order genomic architecture is emerging as an important regulator of gene expression.…”