Investigating the role of SETDB1 in genome architecture maintenance

Abstract

SETDB1, a crucial histone methyltransferase, plays essential roles in mouse development by mediating transcriptional repression of genes and repetitive elements in various cell types through the deposition of histone H3 lysine 9 trimethylation (H3K9me3). However, the specific functions and mechanisms of differential H3K9me3 enrichment across different cell- and tissue-types remains poorly understood. The focus of my research was to uncover the diverse mechanisms and roles of SETDB1 in transcriptional regulation. I observed a global mutual exclusivity between H3K9me3 and CTCF, a key architectural protein, across different mouse tissues from at various developmental stages. To delve into the underlying mechanisms, I utilized SETDB1-depleted mouse embryonic stem cells (ESCs) and discovered that H3K9me3 prevents aberrant CTCF binding independently of DNA methylation through chromatin compaction. Specifically, these sites were exhibited enrichment of SINE B2, which are retrotransposons not previously recognized as targets of SETDB1. While the overall higher-order chromatin structures, including topologically associating domains (TADs) and subnuclear compartments, remained intact, chromatin loops and local interactions were disrupted. These perturbations resulted in transcriptional changes by altering the pre-existing chromatin landscapes, where the relocation of specific genes to dysregulated cis-regulatory elements was observed. Collectively, I found that cell-type specific targets of SETDB1 contributed to maintaining cellular identities through shaping genome architecture and transcriptomic networks. This novel function for SETDB1 and H3K9me3 sheds light on the intricate mechanism between the 3D genome organization and transcriptional regulation. This provide insights into how the regulation of higher-order chromatin structures is pertinent to developmental disorders and cancers with aberrant SETDB1 expression.

Date of Award	2024
Original language	English
Awarding Institution	The Hong Kong University of Science and Technology
Supervisor	Danny Chi Yeu LEUNG (Supervisor)