H3K9me3-Dependent Heterochromatin: Barrier to Cell Fate Changes

H3K9me3, a histone modification associated with heterochromatin, contributes to gene regulation by forming large repressive domains on the chromosomes that can be dynamic in mammalian development. H3K9me3 domains in chromatin prevent binding by diverse transcription factors and constitute a major barrier to reprogram cell identity either by transcription factor overexpression or by somatic cell nuclear transfer. H3K9me3 deposition provides a restriction on developmental potency in the early embryo and promotes the stability of specific differentiated cell fates. Transcription factors and noncoding RNAs have been found to recruit H3K9me3 to particular genomic locations, but a thorough accounting of the mechanisms of tissue-specific variation in H3K9me3 domains is lacking. Establishing and maintaining cell identity depends on the proper regulation of gene expression, as specified by transcription factors and reinforced by epigenetic mechanisms. Among the epigenetic mechanisms, heterochromatin formation is crucial for the preservation of genome stability and the cell type-specific silencing of genes. The heterochromatin-associated histone mark H3K9me3, although traditionally associated with the noncoding portions of the genome, has emerged as a key player in repressing lineage-inappropriate genes and shielding them from activation by transcription factors. Here we describe the role of H3K9me3 heterochromatin in impeding the reprogramming of cell identity and the mechanisms by which H3K9me3 is reorganized during development and cell fate determination. Establishing and maintaining cell identity depends on the proper regulation of gene expression, as specified by transcription factors and reinforced by epigenetic mechanisms. Among the epigenetic mechanisms, heterochromatin formation is crucial for the preservation of genome stability and the cell type-specific silencing of genes. The heterochromatin-associated histone mark H3K9me3, although traditionally associated with the noncoding portions of the genome, has emerged as a key player in repressing lineage-inappropriate genes and shielding them from activation by transcription factors. Here we describe the role of H3K9me3 heterochromatin in impeding the reprogramming of cell identity and the mechanisms by which H3K9me3 is reorganized during development and cell fate determination. large regions of the genome that are not targeted by iPS reprogramming transcription factors (Oct4, Sox2, Klf4, and c-Myc) in terminally differentiated fibroblasts, but allow binding by the factors in human ES cells, thus impeding efficient reprogramming in fibroblasts. These domains correspond to regions marked by H3K9me3 [32Soufi A. et al.Facilitators and impediments of the pluripotency reprogramming factors’ initial engagement with the genome.Cell. 2012; 151: 994-1004Abstract Full Text Full Text PDF PubMed Scopus (320) Google Scholar]. undifferentiated cells derived from the inner cell mass of the early embryo, which can be cultured in vitro and give rise to any cell type in the embryo. trimethylation of histone 3 lysine 9, a chemical modification of the histone proteins around which DNA is wrapped. H3K9me3-marked chromatin is associated with inhibition of gene transcription. regions of the chromosomes that are especially compacted and transcriptionally repressed. Heterochromatin can be ‘constitutive’ (meaning present in all cell types and phases of the cell cycle) or ‘facultative’ (meaning that repression is cell type-specific or cell cycle phase-specific). proteins required for heterochromatin formation that bind methylated H3K9 via their chromodomain. HP1 proteins act as a scaffold, interacting with H3K9me-related methyltransferases and other proteins via the chromo shadow domain. a cell that has been reverted from a differentiated state to an embryonic stem cell-like state, by overexpression of specific transcription factors. C2H2 zinc finger transcription factors containing an N-terminus KRAB domain, leading to transcriptional repression of genes and recruitment of H3K9me3 upon binding to corepressor proteins. RNA molecules that are not translated into proteins but can be involved in a variety of cellular processes including regulation of gene activity. the property of being able to give rise to all tissue types in the embryo. DNA sequences with high copy numbers organized in adjacent near-identical units (tandem repeats: satellite repeats at telomeres and centromeres) or dispersed throughout the genome (DNA transposons, retrotransposons, and endogenous retroviruses). erasure of epigenetic states converting a differentiated cell into a different type of cell, such as a pluripotent stem cell. regions of the genome containing genes active in normal two-cell mouse embryos but repressed in embryos derived by somatic cell nuclear transfer, indicating that the reprogramming process was incomplete [74Matoba S. et al.Embryonic development following somatic cell nuclear transfer impeded by persisting histone methylation.Cell. 2014; 159: 884-895Abstract Full Text Full Text PDF PubMed Scopus (84) Google Scholar]. laboratory technique in which the nucleus of a differentiated cell is transferred to the cytoplasm of an enucleated egg. Maternal components reprogram the donor nucleus to pluripotency, allowing the generation of cloned organisms.