Suv39h-catalyzed H3K9me3 is critical for euchromatic genome organization and the maintenance of gene transcription

Christine R. Keenan; Hannah D. Coughlan; Nadia Iannarella; Andres Tapia del Fierro; Andrew Keniry; Timothy M. Johanson; Wing Fuk Chan; Alexandra L. Garnham; Lachlan W. Whitehead; Marnie E. Blewitt; Gordon K. Smyth; Rhys S. Allan

doi:10.1101/gr.279119.124

Suv39h-catalyzed H3K9me3 is critical for euchromatic genome organization and the maintenance of gene transcription

¹The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, 3052, Australia;
²Department of Medical Biology, The University of Melbourne, Parkville, Victoria, 3010, Australia;
³School of Mathematics and Statistics, The University of Melbourne, Parkville, Victoria, 3010, Australia

↵4 These authors contributed equally to this work.
↵5 These authors contributed equally to this work.

↵Present addresses: ⁶Department of Biochemistry and Pharmacology, The University of Melbourne, Parkville, Victoria, 3010, Australia; ⁷Australian Centre for Blood Diseases, Monash University, Melbourne, Victoria, 3004, Australia

Corresponding authors: keenanc{at}unimelb.edu.au, rallan{at}wehi.edu.au

Abstract

H3K9me3-dependent heterochromatin is critical for the silencing of repeat-rich pericentromeric regions and also has key roles in repressing lineage-inappropriate protein-coding genes in differentiation and development. Here, we investigate the molecular consequences of heterochromatin loss in cells deficient in both SUV39H1 and SUV39H2 (Suv39DKO), the major mammalian histone methyltransferase enzymes that catalyze heterochromatic H3K9me3 deposition. We reveal a paradoxical repression of protein-coding genes in Suv39DKO cells, with these differentially expressed genes principally in euchromatic (Tn5-accessible, H3K4me3- and H3K27ac-marked) rather than heterochromatic (H3K9me3-marked) or polycomb (H3K27me3-marked) regions. Examination of the three-dimensional (3D) nucleome reveals that transcriptomic dysregulation occurs in euchromatic regions close to the nuclear periphery in 3D space. Moreover, this transcriptomic dysregulation is highly correlated with altered 3D genome organization in Suv39DKO cells. Together, our results suggest that the nuclear lamina-tethering of Suv39-dependent H3K9me3 domains provides an essential scaffold to support euchromatic genome organization and the maintenance of gene transcription for healthy cellular function.

Footnotes

[Supplemental material is available for this article.]
Article published online before print. Article, supplemental material, and publication date are at https://www.genome.org/cgi/doi/10.1101/gr.279119.124.
Freely available online through the Genome Research Open Access option.

Received February 16, 2024.
Accepted April 3, 2024.

This article, published in Genome Research, is available under a Creative Commons License (Attribution-NonCommercial 4.0 International), as described at http://creativecommons.org/licenses/by-nc/4.0/.