Cell-type differential targeting of Setdb1 prevents aberrant CTCF binding, chromatin looping, and cis-regulatory interactions

ABSTRACT: SETDB1 is a histone methyltransferase with essential roles in mouse development. It mediates transcriptional repression of genes and repetitive elements in different cell-types by depositing histone H3 lysine 9 trimethylation (H3K9me3). However, the function of differential H3K9me3 enrichment between cell- and tissue-types remains unclear. In this study, we demonstrate a global mutual exclusivity of H3K9me3 and CTCF across mouse tissues from different developmental time points. To investigate the mechanistic relationship, we analyzed SETDB1 depleted mouse embryonic stem cells and discovered that H3K9me3 prevents aberrant CTCF binding independently of DNA methylation and H3K9me2. Such sites are enriched with retrotransposons such as SINE B2 elements, which are not previously defined as targets of SETDB1. While the epigenetic modifier is known to silence transcriptional enhancers, its effects on higher-order chromatin structures have not been clearly defined. Overall, large chromatin structures including topologically associated domains and subnuclear compartments, remain intact. However, chromatin loops and local interactions are disrupted. Such perturbations lead to transcriptional changes by altering pre-existing chromatin landscapes, where specific genes have differential interactions with dysregulated cis-regulatory elements. This mode of transcriptional regulation is distinct from the direct repression of genic promoters or enhancers. Collectively, we find that cell-type specific targets of SETDB1 contributes to maintaining cellular identities through shaping genome architecture and transcriptomic networks by modulating CTCF binding, representing a novel function for SETDB1 and H3K9me3.

ORGANISM(S): Mus musculus

PROVIDER: GSE184471 | GEO | 2023/11/01

REPOSITORIES: GEO