G9a is a lysine methyltransferase that regulates epigenetic modifications, transcription, and genome organization. However, whether these properties are dependent on one another or represent distinct functions of G9a remains unclear. In this study, we observe widespread DNA methylation loss in G9a depleted and catalytic mutant embryonic stem cells. Furthermore, we define how G9a regulates chromatin accessibility, epigenetic modifications, and transcriptional silencing in both catalytic-dependent and -independent manners. Reactivated retrotransposons provide alternative promoters and splice sites leading to the upregulation of neighboring genes and the production of chimeric transcripts. Moreover, while topologically associated domains and compartment A/B definitions are largely unaffected, the loss of G9a leads to altered chromatin states, aberrant CTCF and cohesin binding, and differential chromatin looping, especially at retrotransposons. Taken together, our findings reveal how G9a regulates the epigenome, transcriptome, and higher-order chromatin structures in distinct mechanisms.
Keywords: CTCF; Cohesin; DNA methylation; G9a; chromatin loops; epigenome; genome architecture; histone modifications; retrotransposons.
Copyright © 2020 The Author(s). Published by Elsevier Inc. All rights reserved.