Ten principles of heterochromatin formation and function

Abstract

Heterochromatin is a key architectural feature of eukaryotic chromosomes, which endows particular genomic domains with specific functional properties. The capacity of heterochromatin to restrain the activity of mobile elements, isolate DNA repair in repetitive regions and ensure accurate chromosome segregation is crucial for maintaining genomic stability. Nucleosomes at heterochromatin regions display histone post-translational modifications that contribute to developmental regulation by restricting lineage-specific gene expression. The mechanisms of heterochromatin establishment and of heterochromatin maintenance are separable and involve the ability of sequence-specific factors bound to nascent transcripts to recruit chromatin-modifying enzymes. Heterochromatin can spread along the chromatin from nucleation sites. The propensity of heterochromatin to promote its own spreading and inheritance is counteracted by inhibitory factors. Because of its importance for chromosome function, heterochromatin has key roles in the pathogenesis of various human diseases. In this Review, we discuss conserved principles of heterochromatin formation and function using selected examples from studies of a range of eukaryotes, from yeast to human, with an emphasis on insights obtained from unicellular model organisms.

Heterochromatin Protein HP1α Gelation Dynamics Revealed by Solid‐State NMR Spectroscopy

“…To complement the INEPT-TOBSY 2D correlation experiment, we also recorded a2 DC P-DARR [33] (dipolarassisted rotational resonance) correlation spectrum, which enables transfer between dipolar-coupled, and hence more rigid, 13 Cspin systems (Figures 2cand 3a). Avisual inspection of the complete DARR and INEPT-TOBSY spectra illustrates the dramatic difference in content and linewidths for the two sets of targeted residues (Figure 3a).…”

“…[12,13] HP1a is composed of two folded domains,t he chromodomain (CD) that binds methylated histone H3K9, and the chromoshadow domain (CSD) that enables the formation of the stable 44 kDa HP1a dimer (Figure 1a). [12,13] HP1a is composed of two folded domains,t he chromodomain (CD) that binds methylated histone H3K9, and the chromoshadow domain (CSD) that enables the formation of the stable 44 kDa HP1a dimer (Figure 1a).…”

Evaluation of entinostat alone and in combination with standard‐of‐care cytotoxic agents against rhabdomyosarcoma xenograft models

“…Transcription is regulated by many posttranslational processes, including methylation and acetylation of histones. These processes are mediated by histone lysine methyltransferases (KMTs) and demethylases (KDMs) and histone acetyltransferases (HATs) and deacetylases (HDACs) that balance access of transcriptional machinery required to initiate and elongate mRNA molecules leading to efficient transcription . In simplistic terms, the state of acetylation of histones dictates the open chromatin formation that is transcriptionally active .…”

“…In contrast, H3K9 methylation and trimethylation of H3K27 and H4K20 mark repressed genes. H3K9ac is associated with active gene promoters in association with H3K4me3, and may be involved in the recruitment of bromodomain protein 4 (BRD4) and to mediate POLII pause release from promoter proximal regions, allowing mRNA elongation …”

“…HDACs remove acetyl marks from histones and other proteins, such as transcription factors (TP53, NF‐κB, GATA‐1, and Bcl‐6) Ku70, Hsp90, and α‐tubulin and in general lead to suppression of gene expression . Eighteen HDACs have been identified and are classified based on their structural conservation.…”