A Mediator-cohesin axis controls heterochromatin domain formation

Judith H I Haarhuis,Hans Teunissen,Vincent A Blomen,Koen D Flach,Laureen Willems,Benjamin D Rowland,Elzo De Wit,Thijn R Brummelkamp,Robin H Van Der Weide

doi:10.1038/s41467-022-28377-7

Abstract

The genome consists of regions of transcriptionally active euchromatin and more silent heterochromatin. We reveal that the formation of heterochromatin domains requires cohesin turnover on DNA. Stabilization of cohesin on DNA through depletion of its release factor WAPL leads to a near-complete loss of heterochromatin domains. We observe the opposite phenotype in cells deficient for subunits of the Mediator-CDK module, with an almost binary partition of the genome into dense H3K9me3 domains, and regions devoid of H3K9me3 spanning the rest of the genome. We suggest that the Mediator-CDK module might contribute to gene expression by limiting the formation of dense heterochromatin domains. WAPL deficiency prevents the formation of heterochromatin domains, and allows for gene expression even in the absence of the Mediator-CDK subunit MED12. We propose that cohesin and Mediator affect heterochromatin in different ways to enable the correct distribution of epigenetic marks, and thus to ensure proper gene expression.

Highlights

The genome consists of regions of transcriptionally active euchromatin and more silent heterochromatin
We have previously shown that the stabilization of cohesin on chromatin has a major effect on the 3D genome
Loss of the cohesin-release factor WAPL leads to a genome-wide increase in the length and number of CTCF-anchored loops[9,16]

Summary

A Mediator-cohesin axis controls heterochromatin domain formation

We suggest that the Mediator-CDK module might contribute to gene expression by limiting the formation of dense heterochromatin domains. WAPL deficiency prevents the formation of heterochromatin domains, and allows for gene expression even in the absence of the Mediator-CDK subunit MED12. Within the nucleus active and inactive genomic regions segregate into euchromatin and heterochromatin. The latter is molecularly defined by the post-translational methylation of the ninth lysine of histone H3 (H3K9me)[1,2]. We explore the role of chromatin loop formation and compartmentalization in the control of the epigenome and the expression of genes. Loss of the Mediator complex CDK-module subunits MED12 and CCNC on the other hand increases both compartmentalization and heterochromatin domain formation. We conclude that a Mediatorcohesin axis controls both the spatial and the linear epigenome

Results and discussion

Methods

Code availability