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Review
. 2021 Oct;67(5):695-705.
doi: 10.1007/s00294-021-01196-x. Epub 2021 Jun 5.

New connections between ubiquitylation and methylation in the co-transcriptional histone modification network

Daniel Pinto  1 , Vivane Pagé  1 , Robert P Fisher  2 , Jason C Tanny  3
Affiliations
Review

New connections between ubiquitylation and methylation in the co-transcriptional histone modification network

Daniel Pinto et al. Curr Genet. 2021 Oct.

Abstract

Co-transcriptional histone modifications are a ubiquitous feature of RNA polymerase II (RNAPII) transcription, with profound but incompletely understood effects on gene expression. Unlike the covalent marks found at promoters, which are thought to be instructive for transcriptional activation, these modifications occur in gene bodies as a result of transcription, which has made elucidation of their functions challenging. Here we review recent insights into the regulation and roles of two such modifications: monoubiquitylation of histone H2B at lysine 120 (H2Bub1) and methylation of histone H3 at lysine 36 (H3K36me). Both H2Bub1 and H3K36me are enriched in the coding regions of transcribed genes, with highly overlapping distributions, but they were thought to work largely independently. We highlight our recent demonstration that, as was previously shown for H3K36me, H2Bub1 signals to the histone deacetylase (HDAC) complex Rpd3S/Clr6-CII, and that Rpd3S/Clr6-CII and H2Bub1 function in the same pathway to repress aberrant antisense transcription initiating within gene coding regions. Moreover, both of these histone modification pathways are influenced by protein phosphorylation catalyzed by the cyclin-dependent kinases (CDKs) that regulate RNAPII elongation, chiefly Cdk9. Therefore, H2Bub1 and H3K36me are more tightly linked than previously thought, sharing both upstream regulatory inputs and downstream effectors. Moreover, these newfound connections suggest extensive, bidirectional signaling between RNAPII elongation complexes and chromatin-modifying enzymes, which helps to determine transcriptional outputs and should be a focus for future investigation.

Keywords: Co-transcriptional histone modification; H2Bub1; H3K36me.

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Conflict of interest statement

Conflict of interest The authors declare no conflicts of interest.

Figures

Fig. 1
Fig. 1
Landscape of histone modifications (A) and CDK-dependent phosphorylations (B) in and around RNAPII transcription units. TSS, transcription start site; PAS, polyadenylation site. See text for details
Fig. 2
Fig. 2
Interaction surfaces for Set2, Dot1, and COMPASS/MLL on the nucleosome. Sites of interaction (circles) and relevant histone modification sites (red dots) are highlighted on a model of the nucleosome crystal structure (PDB 1KX5). In this view, COMPASS/MLL and Set2 methylate the histone H3 monomer on the left side of the dyad axis (coloured red), whereas Dot1 methylates the histone H3 monomer on the right (coloured brown)
Fig. 3
Fig. 3
H2Bub1 preferentially activates genes in subtelomeric “knob” domains. A Fraction of H2Bub1-activated genes (defined by RNA-seq in ref 49) within the indicated genomic intervals. Significant enrichment within subtelomeric regions was assessed by hypergeometric test. B Expression of the knob gene aes1+ or the heterochomatic gene tlh1+ was determined by RT-qPCR as in ref in the indicated strains; values in the wild-type strain were set to 1. Asterisks denote significant differences from wild-type (n = 3; unpaired t test with Bonferroni correction; p < 0.05). C Expression of the indicated knob genes was determined by RT-qPCR in the indicated strains and normalized to act1+ expression as in ref . Asterisks denote significant differences from wild-type (n = 4; unpaired t-test with Bonferroni correction; p < 0.05). Primer sequences are available upon request
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