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H3K9me3-heterochromatin loss at protein-coding genes enables developmental lineage specification

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Science  18 Jan 2019:
Vol. 363, Issue 6424, pp. 294-297
DOI: 10.1126/science.aau0583

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Reversing chromatin dynamics for development

Compacted chromatin regions, marked by trimethylation of histone H3 at position lysine 9 (H3K9me3), occur at highly repeated DNA sequences, helping to suppress recombination and gene expression. Because pluripotent cells contain low levels of H3K9me3 heterochromatin relative to differentiated cells, it has been thought that an increase in such heterochromatin helps to define cell differentiation. Nicetto et al. used two independent methods to examine compacted heterochromatic domains and found that H3K9me3 compaction increased at protein-coding genes during early mouse organogenesis. During differentiation, these domains open up to allow cell-specific expression. Loss of heterochromatin by genetic inactivation of the H3K9me3 methyltransferases caused ectopic expression of cell-inappropriate genes and tissue pathology.

Science, this issue p. 294

Abstract

Gene silencing by chromatin compaction is integral to establishing and maintaining cell fates. Trimethylated histone 3 lysine 9 (H3K9me3)–marked heterochromatin is reduced in embryonic stem cells compared to differentiated cells. However, the establishment and dynamics of closed regions of chromatin at protein-coding genes, in embryologic development, remain elusive. We developed an antibody-independent method to isolate and map compacted heterochromatin from low–cell number samples. We discovered high levels of compacted heterochromatin, H3K9me3-decorated, at protein-coding genes in early, uncommitted cells at the germ-layer stage, undergoing profound rearrangements and reduction upon differentiation, concomitant with cell type–specific gene expression. Perturbation of the three H3K9me3-related methyltransferases revealed a pivotal role for H3K9me3 heterochromatin during lineage commitment at the onset of organogenesis and for lineage fidelity maintenance.

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