Chromatin architecture reorganization during stem cell differentiation

Abstract

Higher order chromatin structure is emerging as an important regulator of gene expression. Although dynamic chromatin structures have been identified in the genome, the full scope of chromatin dynamics during mammalian development and lineage specification remains obscure. By mapping genome-wide chromatin interactions in human embryonic stem cells (hESC) and four hESC-derived lineages, we uncover extensive chromatin reorganization during lineage specification. We observe that while topological domain boundaries remain intact during differentiation, interactions both within and between domains change dramatically, altering 36% of active and inactive chromosomal “compartments” throughout the genome. By integrating chromatin interaction maps with haplotype-resolved epigenome and transcriptome datasets, we find widespread allelic bias in gene expression correlated with allele-biased chromatin states of linked promoters and distal enhancers. Our results therefore provide a global view of chromatin dynamics and a resource for studying long-range control of gene expression in distinct human cell lineages.

Impact of the gut microbiota on enhancer accessibility in gut intraepithelial lymphocytes

“…Although increases in chromatin accessibility correlate with transcriptional activity, these measurements are limited in their ability to characterize more complex modulations of the chromatin state. For instance, enhancers can be poised or active (45), and the recruitment of chromatin regulators at preexisting accessible sites can dramatically modulate transcriptional responses (46)(47)(48). Nonresponsive enhancers, which fail to exhibit alterations in chromatin accessibility after delayed exposure to a microbiota, could reflect (i) the existence of a critical developmental window beyond which chromatin modification is not possible or is unlikely; (ii) the need for a minimal length of time of microbial exposure, irrespective of when the microbiota is first introduced, that was not satisfied under our experimental conditions (5 wk of exposure starting at the end of postnatal week 3); or (iii) differences in the structural and functional configuration of the microbiota that we observed between CONV-R and CONV-D animals.…”

Nucleosome positioning changes during human embryonic stem cell differentiation

“…Function-wise, while silenced genes encode many known and putative pluripotent markers, activated genes are significantly enriched in ECM-associated groups. A recent study 56 reports that during hESC differentiation, genes that have undergone A/B chromatin compartment switching and show correlated gene expression changes are mostly ECM-related and have low GCC content at their Table S5A. (B) Genomic regions with higher nucleosome occupancy have more C$G substitutions and fewer T$A substitutions, compared to those with lower nucleosome occupancy.…”

Roadmap for regulation

“…The authors found that these variants are often located in or near enhancers [2][3][4][5][6][7][8][9] , and encompassing embryonic and adult tissues, from healthy individuals and those with disease. a, Many of the adult tissues investigated were broken down by cell type or region -blood into several types of immune cell, for instance, and the brain into regions including the hippocampus and dorsolateral prefrontal cortex.…”

“…Dixon et al 9 (page 331) investigated this phenomenon, charting changes in three-dimensional (3D) chromatin organization during stem-cell differentiation. Human cells contain two copies, or alleles, of each gene, which can vary in terms of DNA sequence, resulting in differences in transcriptional activity (allele-restricted transcription).…”