Control of Cell Identity Genes Occurs in Insulated Neighborhoods in Mammalian Chromosomes

Abstract

SUMMARY The pluripotent state of embryonic stem cells (ESCs) is produced by active transcription of genes that control cell identity and repression of genes encoding lineage-specifying developmental regulators. Here we use ESC cohesin ChIAPET data to identify the local chromosomal structures at both active and repressed genes across the genome. The results produce a map of enhancer-promoter interactions and reveal that super-enhancer driven genes generally occur within chromosome structures that are formed by the looping of two interacting CTCF sites co-occupied by cohesin. These looped structures form insulated neighborhoods whose integrity is important for proper expression of local genes. We also find that repressed genes encoding lineage-specifying developmental regulators occur within insulated neighborhoods. These results provide new insights into the relationship between transcriptional control of cell identity genes and control of local chromosome structure.

Enhancer priming by H3K4 methyltransferase MLL4 controls cell fate transition

“…In addition, RNA polymerase II (Pol II) binds to AEs and transcribes enhancer DNAs into enhancer RNAs (eRNAs) (16). Consistent with the Chromatin Interaction Analysis by Paired-End Tag Sequencing (ChIA-PET) data obtained from a previous study (12), Chromatin Conformation Capture (3C) assays confirmed that MLL4 + AEs formed loops with promoters on Nanog and Lefty1 loci. Mll4 deletion had little impact on the interaction between MLL4-independent AE and promoter on Nanog locus but significantly attenuated the interaction between MLL4-dependent AE and promoter on Lefty1 locus (Fig.…”

In Vitro Modeling of Complex Neurological Diseases

“…These analyses suggest that active enhancer elements are bound by transcription factors and loop over long distances to contact target genes to regulate transcription. An emerging model suggests promoter-enhancer interactions typically only occur within megabase-sized topological-associated domains (TAD; Dixon et al 2012;Nora et al 2012), as defined by high DNA interaction frequency based on genome-wide chromosome capture data or within such TADs in insulated neighborhoods restricted by cohesin-associated CTCF-CTCF loops (Handoko et al 2011;DeMare et al 2013;Dowen et al 2014;Rao et al 2014;Ji et al 2016). Notably, there is mounting evidence that changes in 3D structure, potentially through sequence-specific disruption of CTCF interaction, might contribute to disease development (Ji et al 2016).…”

“…The recent development of chromosome conformation capture techniques ("3C" and genome-wide 3C-based methods; Dekker et al 2002Dekker et al , 2013 or cohesin chromatin interaction analysis by paired-end tag sequencing (ChIA-PET; Dowen et al 2014) allow us to determine long-range chromatin interactions such as cell type-specific promoter-enhancer interaction. These analyses suggest that active enhancer elements are bound by transcription factors and loop over long distances to contact target genes to regulate transcription.…”

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

“…The structure created by chromosome loops is conserved across cell types and species providing scaffolding for enhancer-promoter interactions. In ESCs, enhancerpromoter cross talks occur within chromosome loops flanked by two interacting CTCF [14,15]. This type of insulated chromatin organization is important for proper coregulation of lineage-specific developmental genes.…”

“…Although CTCF defines the borders of TADs, divergent CTCF binding between species is correlated with species-specific differences of internal subdomain structures, which is a subject of mutation-driven evolutionary changes that could affect the CTCF recruitment. CTCF often co-occupies genomic regions with cohesin to mediate 3D chromosome looping [15]. The reduced dosage of cohesin alters the genome architecture of the regenerating islet-derived gene cluster and decreases their expression in the pancreas of mice heterozygous for SA1, one of the cohesin subunits [17].…”