Cell Fate Engineering and Therapeutics Lab, Cell Biology and Therapies Division, A*STAR Institute of Molecular and Cell Biology, Singapore 138673, Singapore.
Department of Biological Sciences, National University of Singapore, Singapore 117543, Singapore.
Nucleic Acids Res. 2022 Jul 22;50(13):7326-7349. doi: 10.1093/nar/gkac531.
SETDB1 is a key regulator of lineage-specific genes and endogenous retroviral elements (ERVs) through its deposition of repressive H3K9me3 mark. Apart from its H3K9me3 regulatory role, SETDB1 has seldom been studied in terms of its other potential regulatory roles. To investigate this, a genomic survey of SETDB1 binding in mouse embryonic stem cells across multiple libraries was conducted, leading to the unexpected discovery of regions bereft of common repressive histone marks (H3K9me3, H3K27me3). These regions were enriched with the CTCF motif that is often associated with the topological regulator Cohesin. Further profiling of these non-H3K9me3 regions led to the discovery of a cluster of non-repeat loci that were co-bound by SETDB1 and Cohesin. These regions, which we named DiSCs (domains involving SETDB1 and Cohesin) were seen to be proximal to the gene promoters involved in embryonic stem cell pluripotency and lineage development. Importantly, it was found that SETDB1-Cohesin co-regulate target gene expression and genome topology at these DiSCs. Depletion of SETDB1 led to localized dysregulation of Cohesin binding thereby locally disrupting topological structures. Dysregulated gene expression trends revealed the importance of this cluster in ES cell maintenance as well as at gene 'islands' that drive differentiation to other lineages. The 'unearthing' of the DiSCs thus unravels a unique topological and transcriptional axis of control regulated chiefly by SETDB1.
SETDB1 通过其抑制性 H3K9me3 标记的沉积，成为谱系特异性基因和内源性逆转录病毒元件（ERVs）的关键调节因子。除了其 H3K9me3 调节作用外，SETDB1 在其他潜在调节作用方面的研究甚少。为了研究这一点，在多个文库中对 SETDB1 在小鼠胚胎干细胞中的结合进行了基因组调查，导致了一个意想不到的发现，即缺乏常见抑制性组蛋白标记（H3K9me3、H3K27me3）的区域。这些区域富含 CTCF 基序，通常与拓扑调节剂 Cohesin 相关。对这些非 H3K9me3 区域的进一步分析导致发现了一组由 SETDB1 和 Cohesin 共同结合的非重复基因座簇。我们将这些区域命名为 DiSCs（涉及 SETDB1 和 Cohesin 的区域），它们靠近参与胚胎干细胞多能性和谱系发育的基因启动子。重要的是，发现 SETDB1-Cohesin 共同调节这些 DiSCs 上的靶基因表达和基因组拓扑结构。SETDB1 的缺失导致 Cohesin 结合的局部失调，从而局部破坏拓扑结构。失调的基因表达趋势揭示了这个基因簇在 ES 细胞维持以及驱动向其他谱系分化的基因“岛”中的重要性。因此，DiSCs 的“挖掘”揭示了主要由 SETDB1 调节的独特的拓扑和转录控制轴。
