ALL STEM CELLS

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 to be determined. By mapping genome-wide chromatin interactions in human embryonic stem(ES) cells and four human ES-cell-derived lineages, we uncover extensive chromatin reorganization during lineage specification. We observe that although self-associating chromatin domains are stable during differentiation, chromatin interactions both within and between domains change in a striking manner, altering 36% of active and inactive chromosomal compartments throughout the genome. By integrating chromatin interaction maps with haplotype-resolved epigenome and transcriptome data sets, 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.

Discussion
We have presented genome-wide chromatin interaction maps in H1 human ES cells and four H1-derived lineages.We observed dynamic reorganization of higher-order chromatin structure during ES cell differentiation at multiple hierarchical scales. We found extensive switching between the A and B compartments during ES cell differentiation, and observed that distinct subsets of genes have concordant A/B compartments status and expressionlevels. In this regard, these results are similar to what has been seenwith nuclear lamina tethering studies, where the expression of only a subset of genes is affected by compartment changes, while other genes remain unaffected.Changes in compartment status may influence the accessibility of genomic regions to transcription factors or other regulatory proteins, which may be particularly important for certain subsets of genes.
In addition,we have observed local alterations in chromatin interaction frequency within TADs. These local changes are best predicted by changes in levels of H3K4me1 and the density of enhancer elements. This is in agreement with recent 5C studies demonstrating that cell-type specific interaction regions are enriched for Smc1, mediator, and transcription factor binding sites. Taken together, these results suggest that enhancer elements likely play an important role in shaping local higher-order chromatin structure throughout the genome. In addition, by analysing patterns of chromatin interactions on each parental allele, we observe relativelyminor global changes in higher-order chromatin structure between alleles. The chromatin interaction maps generated in this study also allowed the reconstruction of chromosome-span haplotypes for the H1 genome.
This data set represents one of the first studies of allele-biased expression across multiple cell types of a single individual, as well as analysis of chromatin state at the linked cis regulatory elements. Our data set will serve as a valuable tool for the community to better understand the gene regulatory networks controlling pluripotency and differentiation of human embryonic stem cells.

SOURCE : NATURE MAGAZINE 19, Feb, 2015