Spreading and epigenetic inheritance of heterochromatin require a critical density of histone H3 lysine 9 tri-methylation

Abstract

Heterochromatin assembly requires methylation of histone H3 lysine 9 (H3K9me) and serves as a paradigm for understanding the importance of histone modifications in epigenetic genome control. Heterochromatin is nucleated at specific genomic sites and spreads across extended chromosomal domains to promote gene silencing. Moreover, heterochromatic structures can be epigenetically inherited in a self-templating manner, which is critical for stable gene repression. The spreading and inheritance of heterochromatin are believed to be dependent on preexisting H3K9 tri-methylation (H3K9me3), which is recognized by the histone methyltransferase Clr4/Suv39h via its chromodomain, to promote further deposition of H3K9me. However, the process involving the coupling of the “read” and “write” capabilities of histone methyltransferases is poorly understood. From an unbiased genetic screen, we characterize a dominant-negative mutation in histone H3 (H3G13D) that impairs the propagation of endogenous and ectopic heterochromatin domains in the fission yeast genome. H3G13D blocks methylation of H3K9 by the Clr4/Suv39h methyltransferase and acts in a dosage-dependent manner to interfere with the spreading and maintenance of heterochromatin. Our analyses show that the incorporation of unmethylatable histone H3G13D into chromatin decreases H3K9me3 density and thereby compromises the read-write capability of Clr4/Suv39h. Consistently, enhancing the affinity of Clr4/Suv39h for methylated H3K9 is sufficient to overcome the defects in heterochromatin assembly caused by H3G13D. Our work directly implicates methylated histones in the transmission of epigenetic memory and shows that a critical density threshold of H3K9me3 is required to promote epigenetic inheritance of heterochromatin through the read-write mechanism.

Mitotically heritable, RNA polymerase II-independent H3K4 dimethylation stimulates INO1 transcriptional memory

“…Regardless, our current understanding suggests that the duration of memory relates to limits on inheritance following each round of DNA replication. Whereas H3K9 methylation or H3K27 methylation generally covers tens to hundreds of thousands of base pairs ( Barski et al, 2007 ; Cutter DiPiazza et al, 2021 ; Pauler et al, 2009 ; Yu et al, 2014 ), the chromatin changes associated with epigenetic transcriptional memory are more local, covering hundreds of base pairs ( D’Urso et al, 2016 ). Following DNA replication, nucleosomes are randomly segregated into the two daughter molecules ( Petryk et al, 2018 ; Yu et al, 2018 ).…”

“…Approximately half of the nucleosomes should retain regulatory marks and the inheritance of those marks requires recognizing these nucleosomes and modifying adjacent, unmarked nucleosomes ( Escobar et al, 2021 ; Loyola et al, 2006 ). If recognition and/or modification is imperfect, the efficiency of such an inheritance mechanism should increase with the number of nucleosomes ( Cutter DiPiazza et al, 2021 ). If so, then the duration of memory could be limited by a combination of the number of modified nucleosomes, the fidelity, and efficiency of the reader-writer system and the regulation of the initiating transcription factors.…”

Effect of Cold Atmospheric Plasma on Epigenetic Changes, DNA Damage, and Possibilities for Its Use in Synergistic Cancer Therapy

“…The best characterised are histone 3 lysine 4 methylation (H3K4me), histone 3 lysine 9 (H3K9me) and histone 3 lysine 27 methylation (H3K27me). H3K4me enhances transcription and is usually close to gene promoters, while H3K9me and H3K27me inactivate transcription and are mainly associated with heterochromatin [94][95][96][97][98][99]. However, final methylation effects differ depending on the number of methyl groups bound to the histone residue.…”

“…All the above-mentioned methylations are associated with different methyla-transferases and de-methylases, and Hyun described precisely how these coordinate histone methylation [100]. Histone methylation generates motifs recognised and bound by other proteins, especially those with the Chromo, Tudor, MBT and PHD domains [94][95][96][97][98][99]. This protein binding can subsequently affect final transcription activation or inhibition.…”

Editorial: Chromatin Spatial Configuration and Function in Metazoans

“…The authors stress that understanding histone and histone modification retention in spermatids could have deep implications in inter and transgenerational inheritance. This would involve “readers” of histone marks like the chromodomain proteins (Cutter Dipiazza et al, 2021 ), as emphasized by DasGupta et al The authors provide a comprehensive overview of the central function of chromodomain proteins as “readers” and nucleators of diverse protein and RNA complexes regulating gene expression and genome architecture locally and globally in C. elegans .…”