Epigenetic Regulation of Nuclear Lamina-Associated Heterochromatin by HAT1 and the Acetylation of Newly Synthesized Histones

Abstract

During S phase, eukaryotic cells must faithfully duplicate both the sequence of the genome and the regulatory information found in the epigenome. A central component of the epigenome is the pattern of histone post-translational modifications that play a critical role in the formation of specific chromatin states. During DNA replication, parental nucleosomes are disrupted and re-deposited on the nascent DNA near their original location to preserve the spatial memory of the epigenetic modifications. Newly synthesized histones must be also incorporated into the nascent chromatin to maintain nucleosome density. Transfer of modification patterns from parental histones to new histones is a fundamental step in epigenetic inheritance. Whether new histones play an active or passive role in epigenetic inheritance is unknown. Here we report that HAT1, which acetylates lysines 5 and 12 of newly synthesized histone H4 during replication-coupled chromatin assembly, regulates the epigenetic inheritance of chromatin states. HAT1 regulates the accessibility of large domains of heterochromatin termed HAT1-dependent Accessibility Domains (HADs). HADs are mega base-scale domains that comprise ~10% of the mouse genome. HAT1 functions as a global negative regulator of H3 K9me2/3 and HADs correspond to the regions of the genome that display HAT1-dependent increases in H3 K9me3 peak density. HADs display a high degree of overlap with a subset of Lamin-Associated Domains (LADs). HAT1 is required to maintain nuclear structure and integrity and physically associates with the nuclear lamina. These results indicate that HAT1 and the acetylation of newly synthesized histones are critical regulators of the epigenetic inheritance of heterochromatin and suggest a new mechanism for the epigenetic regulation of nuclear lamina-heterochromatin interactions.

The 3D chromatin landscape of rhabdomyosarcoma

“…To our surprise, we also observed substantial signal of H3K27ac and H3K9me3 in both compartmental classes. This is consistent with histone modifications having unique roles in a context-dependent fashion, or with heterochromatin regions being punctuated with activating marks as has been shown by us and observed in other cell types (37,42). The relative enrichments of H3K9me3 in B-compartments were more pronounced in the fusion-negative subtype ( Figure 1e,f , Supplementary Figure S1-S4 ).…”

“…Regions in compartment A are gene-rich and are usually in an "active" local epigenetic state. These regions usually exhibit higher GC-content and contain more active chromatin markers such as H3K27ac (21,36,37). In contrast, regions in compartment B are relatively gene-poor and show higher levels of silent or repressive local epigenetic markers such as H3K9me3 (38,39).…”

Dynamic Reassociation of the Nuclear Lamina with Newly Replicated DNA

“…In regions of constitutive heterochromatin, the newly synthesized histones must also acquire methylation on H3 K9, which is likely to be a prerequisite for association with the nuclear lamina(8). The acetylation state of newly synthesized histones may influence their subsequent methylation as HAT1 and the acetylation of newly synthesized H3 and H4 regulates H3 K9me2/3 in large chromatin domains, termed HADs ( H AT1-dependent A ccessibility D omains), that show significant overlap with LADs(46). Additionally, HDAC2 and HDAC3 are physically associate with the nuclear lamina and may play a role in converting acetylated newly synthesized histones into a form capable of interacting with the nuclear lamina(47,48).…”

Histone acetyltransferase HAM1 interacts with molecular chaperone DNAJA2 and confers immune responses through salicylic acid biosynthetic genes in cassava

“…Posttranslational modification of proteins generally includes ubiquitination, phosphorylation, acetylation, glycosylation and methylation (Lin et al, 2021; Liu et al, 2022; Luo et al, 2017; Verdin & Ott, 2015). Among them, histone acetylation plays an important role in chromosome structural modification and gene expression regulation (Lawrence et al, 2016; Popova et al, 2021; Yang et al, 2020), and the dynamic balance of histone acetylation is jointly modulated by histone deacetylases (HDACs) and histone acetyltransferases (HATs) (Shen et al, 2015). Histone deacetylation mainly inhibits gene transcription by tightening chromatin structure, while histone acetylation promotes transcription by loosening chromatin structure (Lim et al, 2020).…”