The role of H3K36 methylation and associated methyltransferases in chromosome-specific gene regulation

Abstract

In Drosophila, two chromosomes require special mechanisms to balance their transcriptional output to the rest of the genome. These are the male-specific lethal complex targeting the male X chromosome and Painting of fourth targeting chromosome 4. Here, we explore the role of histone H3 methylated at lysine-36 (H3K36) and the associated methyltransferases-Set2, NSD, and Ash1-in these two chromosome-specific systems. We show that the loss of Set2 impairs the MSL complex-mediated dosage compensation; however, the effect is not recapitulated by H3K36 replacement and indicates an alternative target of Set2. Unexpectedly, balanced transcriptional output from the fourth chromosome requires intact H3K36 and depends on the additive functions of NSD and Ash1. We conclude that H3K36 methylation and the associated methyltransferases are important factors to balance transcriptional output of the male X chromosome and the fourth chromosome. Furthermore, our study highlights the pleiotropic effects of these enzymes.

Distinct roles for canonical and variant histone H3 lysine-36 in Polycomb silencing

“…Given that PREs are thought to be multifaceted regulatory modules that can function as repressors or enhancers in different developmental contexts ( 54 , 89 , 90 ), it is intriguing to speculate on other roles that H3.3K36 might play in Hox gene regulation. Our earlier work demonstrates that H3.2 K36R mutants exhibit widespread transcriptomic defects ( 12 ), and mutants for all three H3K36 lysine methyltransferases in Drosophila also produce large changes in gene expression in the larval brain ( 91 ). Given the enrichment of H3.3 in active areas of the genome, one would expect similar dysregulation in H3.3 K36R mutants.…”

Distinct roles for canonical and variant histone H3 lysine 36 in Polycomb silencing

“…Our earlier work demonstrates that H3 . 2 K36R mutants exhibit widespread transcriptomic defects ( 12 ), and mutants for all three H3K36 lysine methyltransferases in Drosophila also produce large changes in gene expression in the larval brain ( 91 ). Given the enrichment of H3.3 in active areas of the genome, one would expect similar dysregulation in H3 .…”

“…Given that PREs are thought to be multifaceted regulatory modules that can function as repressors or enhancers in different developmental contexts ( 54, 89, 90 ), it is intriguing to speculate on other roles that H3.3K36 might play in Hox gene regulation. Our earlier work demonstrates that H3.2 K36R mutants exhibit widespread transcriptomic defects ( 12 ), and mutants for all three H3K36 lysine methyltransferases in Drosophila also produce large changes in gene expression in the larval brain ( 91 ). Given the enrichment of H3.3 in active areas of the genome, one would expect similar dysregulation in H3.3 K36R mutants.…”

Redesigning theDrosophilahistone gene cluster: An improved genetic platform for spatiotemporal manipulation of histone function

“…Subsequently, a histone replacement platform was developed using CRISPR-Cas9-mediated engineering of the HisC locus (Figure 2D), replacing the endogenous histone gene array with two transgenic 5x histone gene arrays (Zhang et al, 2019;Figure 2E). These three gene replacement platforms have been used to greatly expand our understanding of metazoan histone residue function in the context of animal development (Günesdogan et al 2010;Hödl and Basler 2012;Pengelly et al 2013Pengelly et al , 2015McKay et al 2015;Yung et al 2015;Penke et al 2016;Graves et al 2016;Meers et al 2017Meers et al , 2018aArmstrong et al 2018Armstrong et al , 2019Copur et al 2018;Leatham-Jensen et al 2019;Zhang et al 2019;Koreski et al 2020;Finogenova et al 2020;Regadas et al 2021;Lindehell et al 2021;Crain et al 2022;Corcoran and Jacob 2023;Salzler et al 2023).…”