3D Chromosome Regulatory Landscape of Human Pluripotent Cells

Abstract

SUMMARY In this study, we describe the 3D regulatory chromosome structural landscape of human naive and primed embryonic stem cells. To devise this map, we identified transcriptional enhancers and insulators in these cells and placed them within the context of cohesin-associated CTCF-CTCF loops using cohesin ChIA-PET data. The CTCF-CTCF loops we identified form a chromosomal framework of insulated neighborhoods, which in turn form topologically associated domains (TADs), that are largely preserved during transition between the naïve and primed states. Regulatory changes in enhancer-promoter interactions occur within insulated neighborhoods during cell state transition. The CTCF anchor regions we identified are conserved across species, influence gene expression, and are a frequent site of mutations in cancer cells, underscoring their functional importance in cellular regulation. These 3D regulatory maps of human pluripotent cells therefore provide a foundation for future interrogation of the relationships between chromosome structure and gene control in development and disease.

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).…”

“…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). Integrating datasets of cell type-specific changes in enhancer-promoter interactions and information about the 3D structure of the genome will further help us to assign disease-associated risk variants in enhancer sequences to target genes and provide supporting evidence to identify functional disease-associated risk variants and deregulated target genes.…”

Controlling gene expression by DNA mechanics: emerging insights and challenges

“…TADs partition chromosomes into blocks of DNA at scales of hundreds of kilobases to megabases of DNA and are frequently bounded at inverted CTCF-binding sites, suggesting that CTCF-mediated loops comprise a major organizing principle for the genome (Cook and Gove 1992;Dekker and Heard 2015;Dekker and Misteli 2015;Dixon et al 2012;Guo et al 2015;Ji et al 2016;Pope et al 2014;Smith et al 2016;Tang et al 2015;Valton and Dekker 2016). CTCF and cohesin are enriched at TAD boundaries (Guo et al 2015;Ji et al 2016;Katainen et al 2015;Rao et al 2015;Sofueva et al 2013;Tang et al 2015;Xiao et al 2011;Zuin et al 2014).…”

Chromatin and Epigenetics at the Forefront: Finding Clues among Peaks

“…The insulation of TADs is mediated by chromosome-structuring proteins, such as CTCF (15,16). Global analysis of binding factor sequence showed that CTCF sites are among the sequences most frequently altered in human cancer and that these mutations occur frequently near cancer-associated genes (17). Abe Weintraub (from Richard Young's laboratory, MIT, USA) presented recent examples from T-cell acute lymphoblastic leukemia (T-ALL) in which recurrent microdeletions occurred at the boundary sites of insulated neighboring proto-oncogenes, which can drive cellular transformation (18).…”