Department of Cell and Systems Biology, University of Toronto, Toronto, Ontario M55 3G5, Canada.
Institute of Genetics and Molecular and Cellular Biology (IGBMC), UMR7104, Centre National de la Recherche Scientifique, U1258, Institut National de la Santé et de la Recherche Médicale, University of Strasbourg, 6704 Illkirch, France.
Genes Dev. 2022 Jun 1;36(11-12):699-717. doi: 10.1101/gad.349489.122. Epub 2022 Jun 16.
How distal regulatory elements control gene transcription and chromatin topology is not clearly defined, yet these processes are closely linked in lineage specification during development. Through allele-specific genome editing and chromatin interaction analyses of the locus in mouse embryonic stem cells, we found a striking disconnection between transcriptional control and chromatin architecture. We traced nearly all transcriptional activation to a small number of key transcription factor binding sites, whose deletions have no effect on promoter-enhancer interaction frequencies or topological domain organization. Local chromatin architecture maintenance, including at the topologically associating domain (TAD) boundary downstream from the enhancer, is widely distributed over multiple transcription factor-bound regions and maintained in a CTCF-independent manner. Furthermore, partial disruption of promoter-enhancer interactions by ectopic chromatin loop formation has no effect on transcription. These findings indicate that many transcription factors are involved in modulating chromatin architecture independently of CTCF.
远端调控元件如何控制基因转录和染色质拓扑结构尚不清楚，但在发育过程中的谱系特化中，这些过程密切相关。通过对小鼠胚胎干细胞中 基因座的等位基因特异性基因组编辑和染色质相互作用分析，我们发现转录控制和染色质结构之间存在惊人的脱节。我们追踪到几乎所有的 转录激活都与少数关键转录因子结合位点有关，这些结合位点的缺失对启动子-增强子相互作用频率或拓扑结构域组织没有影响。局部染色质结构的维持，包括在 增强子下游的拓扑关联域（TAD）边界，广泛分布在多个转录因子结合区域，并以 CTCF 非依赖性的方式维持。此外，通过异位染色质环形成部分破坏启动子-增强子相互作用对 转录没有影响。这些发现表明，许多转录因子参与调节染色质结构，而不依赖于 CTCF。
