Epigenetic Factors that Control Pericentric Heterochromatin Organization in Mammals

Abstract

Pericentric heterochromatin (PCH) is a particular form of constitutive heterochromatin that is localized to both sides of centromeres and that forms silent compartments enriched in repressive marks. These genomic regions contain species-specific repetitive satellite DNA that differs in terms of nucleotide sequences and repeat lengths. In spite of this sequence diversity, PCH is involved in many biological phenomena that are conserved among species, including centromere function, the preservation of genome integrity, the suppression of spurious recombination during meiosis, and the organization of genomic silent compartments in the nucleus. PCH organization and maintenance of its repressive state is tightly regulated by a plethora of factors, including enzymes (e.g., DNA methyltransferases, histone deacetylases, and histone methyltransferases), DNA and histone methylation binding factors (e.g., MECP2 and HP1), chromatin remodeling proteins (e.g., ATRX and DAXX), and non-coding RNAs. This evidence helps us to understand how PCH organization is crucial for genome integrity. It then follows that alterations to the molecular signature of PCH might contribute to the onset of many genetic pathologies and to cancer progression. Here, we describe the most recent updates on the molecular mechanisms known to underlie PCH organization and function.

The Multiple Facets of ATRX Protein

“…PCH organization and maintenance of its repressive state is tightly regulated by a plethora of factors, including enzymes (e.g., DNA methyltransferases—DNMTs, histone deacetylases—HDACs, and histone methyltransferases—HMTs), DNA and histone methylation binding factors (e.g., MECP2 and HP1), chromatin remodeling proteins (e.g., ATRX), and non-coding RNA (ncRNA) ( Figure 3 ). Histone tails post-translational modifications are crucial events for the preservation of PCH molecular organization and are mediated by the concerted actions of a number of enzymes [ 88 ]. In particular, trimethylation of H3K9 is mediated by the histone methyltransferases (HMT) suppressor of variegation 3–9 homolog 1 and 2 (SUV39H1/2) [ 89 , 90 ] and partially depend on DNA methylation [ 91 ].…”

MeCP2 and Major Satellite Forward RNA Cooperate for Pericentric Heterochromatin Organization

“…In mouse, PCH is composed of hypermethylated 234-bp major satellite ( MajSat ) AT-rich repeats, which form complexes with hypo-acetylated and trimethylated histones H3 and H4 (e.g., H3K9me3, H4K20me3). These histones, in turn, promote anchoring of specific factors, such as members of the heterochromatin protein 1 (HP1) family and the cohesin complex, respectively ( Fioriniello et al., 2020 ). The interactions between PCH regions appear to promote genomic compartmentalization in the nucleus ( Falk et al., 2019 ), and recent findings support the importance of PCH in the formation of repressive compartments where silenced genes are positioned ( Wijchers et al., 2015 ).…”

DAXX Is a Crucial Factor for Proper Development of Mammalian Oocytes and Early Embryos

“…The DAXX protein is a chaperone of the histone variant H3.3 [ 4 , 5 ]. DAXX-dependent deposition of H3.3 and known relations of the DAXX protein with transcription factors, epigenetic modifiers, and chromatin-remodeling proteins including the α-thalassemia/mental retardation syndrome X-linked protein ATRX [ 6 ] make DAXX a main player in chromatin silencing, mainly in the pericentromeric areas [ 7 ]. There is growing recent evidence that mutations in the DAXX gene may be associated with some cancers [ 8 ], suggesting DAXX as one of the most important factors in maintaining the integrity of the genome.…”