Genome-wide Chromatin State Transitions Associated with Developmental and Environmental Cues

Abstract

Differences in chromatin organization are key to the multiplicity of cell states that arise from a single genetic background, yet the landscapes of in vivo tissues remain largely uncharted. Here we mapped chromatin genome-wide in a large and diverse collection of human tissues and stem cells. The maps yield unprecedented annotations of functional genomic elements and their regulation across developmental stages, lineages, and cellular environments. They also reveal global features of the epigenome, related to nuclear architecture, that also vary across cellular phenotypes. Specifically, developmental specification is accompanied by progressive chromatin restriction as the default state transitions from dynamic remodeling to generalized compaction. Exposure to serum in vitro triggers a distinct transition that involves de novo establishment of domains with features of constitutive heterochromatin. We describe how these global chromatin state transitions relate to chromosome and nuclear architecture, and discuss their implications for lineage fidelity, cellular senescence and reprogramming.

Reprogramming of the human intestinal epigenome by surgical tissue transposition

“…The interplay between environmental cues and epigenetic changes has been described at length in the context of cellular development and/or pathogenesis, yet not much is known about the role of the tissue environment in maintaining the epigenome of normal somatic cells (Feil and Fraga 2011;Zhu et al 2013). This is partly because most human studies have been largely limited either to epidemiological approaches, where exposure time is often unknown, or in vitro systems, which, while useful, do not always recapitulate in vivo conditions (Wilson and Jones 1983;Christensen et al 2009;Cortessis et al 2012;Mill and Heijmans 2013;Zhu et al 2013).…”

“…This is partly because most human studies have been largely limited either to epidemiological approaches, where exposure time is often unknown, or in vitro systems, which, while useful, do not always recapitulate in vivo conditions (Wilson and Jones 1983;Christensen et al 2009;Cortessis et al 2012;Mill and Heijmans 2013;Zhu et al 2013). Our study using the human ileal neobladder is the first model that attempts to characterize and quantify the dynamic interaction between the local tissue environment and the epigenetics in vivo.…”

“…Various local environmental factors are known to influence epigenetic programming during mammalian development and contribute to disease susceptibility (Jirtle and Skinner 2007;Feil and Fraga 2011;Gordon et al 2012;Walker and Ho 2012;Zhu et al 2013). The role of the local tissue environment in maintaining normal DNA methylation patterns, and subsequently the cellular phenotype of differentiated human cells, however, has remained elusive as studies in human subjects have mostly been limited to in vitro models and/or epidemiological observations where the extent of environmental exposure is often not precisely known (Feil and Fraga 2011;Rakyan et al 2011;Cortessis et al 2012;Mill and Heijmans 2013).…”

Chromatin stretch enhancer states drive cell-specific gene regulation and harbor human disease risk variants

“…As the journey from pluripotency to terminal cell types traverses a series of commitments, bivalent promoters resolve to a monovalent active or repressed status (27,28). The NIH Epigenome Roadmap recently determined that large heterochromatin domains are established to restrict committed cells from performing off-target functions (28).…”

Nanoscale chromatin profiling of gastric adenocarcinoma reveals cancer-associated cryptic promoters and somatically acquired regulatory elements

“…Most GCs are adenocarcinomas, and recent exome-and whole-genome sequencing studies have revealed new GC driver genes and mutational signatures [2][3][4] . Besides protein-coding genes, somatic changes in regulatory elements located in non-coding genomic regions are also likely contributors to malignancy, as these elements can profoundly influence chromatin structure and gene expression [5][6][7] . Regulatory elements can be altered by epigenetic mechanisms including changes in DNA and histone methylation patterns-in many cancers, these have been associated with methylation-induced transcriptional silencing of tumour suppressor genes 8 , chromosomal instability 9 and loss of imprinting 10 .…”