Control of cell identity genes occurs in insulated neighborhoods in mammalian chromosomes

By J. M. Dowen, Z. Fan, Denes Hnisz, Gang Ren, B. Abraham, Lyndon N. Zhang, A. Weintraub, Jurian Schujiers, Tong Ihn Lee, Keji Zhao and 1 more. Cell, 2014

885 citations recorded by the source corpus.

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.

Subfields: Molecular Biology

View Paper: https://www.semanticscholar.org/paper/adba1ba6efb246150f95bee77c82d8e74a4331ad

How researchers see this paper

The researchers whose trusted networks rank it highest, strongest advocate first. Every researcher gets a different order.

In Molecular Biology

Citations in the corpus

Genomic positional conservation identifies topological anchor point (tap)RNAs linked to developmental loci (2016, background): “…indication of increased and coordinated expression and, although many such loops do not show tissue specificity, other topology-dependent events or finer-scale topological contacts likely regulate tissue-specific and fine-tuned expression (Dowen et al., 2014; Lonfat et al., 2014; Rao et al., 2014).”
Transcriptional Addiction in Cancer (2017, positive): “Two types of ciselements that play prominent roles in cancer biology - SEs and insulators – are discussed here.”
A Compendium of Chromatin Contact Maps Reveal Spatially Active Regions in the Human Genome (2016, neutral): “0052), but not polycomb domains (Dowen et al., 2014; Ji et al., 2016), further underscoring the role of FIREs in active gene regulation (Figure S3d).”
Targeted degradation of CTCF decouples local insulation of chromosome domains from genomic compartmentalization (2017, positive): “It has been proposed that CTCF may confer chromatin barrier activity by opposing the spreading of facultative heterochromatin, thereby demarcating active and inactive chromatin domains (Cuddapah et al., 2009; Dowen et al., 2014) and insulating against position effects (Essafi et al.”
CRISPR Inversion of CTCF Sites Alters Genome Topology and Enhancer/Promoter Function (2015, positive): “Insulator elements play pivotal roles in orchestrating proper long-range DNA-looping interactions between remote enhancers and their cognate promoters via mechanisms that are poorly understood (Dowen et al., 2014; Jia et al., 2014; Narendra et al., 2015; Ong and Corces, 2014).”
YY1 Is a Structural Regulator of Enhancer-Promoter Loops (2017, positive): “…and insulated neighborhoods, tend to insulate enhancers and genes within the CTCF-CTCF loops from elements outside those loops (Dixon et al., 2012; Dowen et al., 2014; Hnisz et al., 2016b; Ji et al., 2016; Lupiáñez et al., 2015; Narendra et al., 2015; Nora et al., 2012; Phillips-Cremins et al.,…”
Ever-changing landscapes: transcriptional enhancers in development and evolution (2016, background): “Formation of TAD Boundaries and CTCF-Mediated Loops Since TAD boundaries appear to restrict both enhancer function (Dowen et al., 2014; Flavahan et al., 2016; Guo et al., 2015; Lupiáñez et al., 2015) and spreading of chromatin marks”
EMT and tumor metastasis (2015, background): “The insulated region created by CTCF does not allow gene expression and most developmentally regulated genes, and stem cell pluripotency genes are regulated this way [143].”
Comparative Hi-C Reveals that CTCF Underlies Evolution of Chromosomal Domain Architecture (2015, positive): “Our data thereby point to a strong correlation between the evolution of CTCF binding and chromosomal structure and extend on our current understanding of contextdependent CTCF binding sites and their specific roles in chromosomal domain architecture (Dixon et al., 2012; Dowen et al., 2014).”
Editing DNA methylation in the mammalian genome (2016, positive): “These observations are consistent with the results obtained when these CTCF sites were deleted (Dowen et al., 2014), and support the notion that methylation of the CTCF binding site interferes with its insulator function.”
CTCF-Mediated Human 3D Genome Architecture Reveals Chromatin Topology for Transcription. (2015, background): “Others have demonstrated deletion and inversion of DNA fragments containing CTCF/cohesin binding sites could disrupt the nearby TAD structure and alter associated gene transcription (Dowen et al., 2014; Guo et al., 2015).”