2022,
Nature Genetics.
DOI:
10.1038/s41588-022-01223-8
Enhancer–promoter interactions and transcription are largely maintained upon acute loss of CTCF, cohesin, WAPL or YY1
Tsung-Han S. Hsieh
, Claudia Cattoglio
, Elena Slobodyanyuk
, Anders S. Hansen
, Xavier Darzacq
, Robert Tjian
Abstract:
Abstract It remains unclear why acute depletion of CTCF (CCCTC-binding factor) and cohesin only marginally affects expression of most genes despite substantially perturbing three-dimensional (3D) genome folding at the level of domains and structural loops. To address this conundrum, we used high-resolution Micro-C and nascent transcript profiling in mouse embryonic stem cells. We find that enhancer–promoter (E–P) interactions are largely insensitive to acute (3-h) depletion of CTCF, cohesin or WAPL. YY1 has been proposed as a structural regulator of E–P loops, but acute YY1 depletion also had minimal effects on E–P loops, transcription and 3D genome folding. Strikingly, live-cell, single-molecule imaging revealed that cohesin depletion reduced transcription factor (TF) binding to chromatin. Thus, although CTCF, cohesin, WAPL or YY1 is not required for the short-term maintenance of most E–P interactions and gene expression, our results suggest that cohesin may facilitate TFs to search for and bind their targets more efficiently.
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2023-01-06 22:21:00
徐炳祥:
#paper doi: 10.1038/s41588-022-01223-8 Nature, 2022, Enhancer-promoter interactions and transcription are largely maintained upon acute loss of CTCF, cohesin, WAPL or YY1。染色质空间构象对基因表达的调控模式目前依然是表观遗传学中一个有争议的话题，在本文中，作者快速降解了几个维持与调控染色质空间构象的重要因子（CTCF，cohesin，YY1）并测量了他们对染色质空间构象和基因表达谱的冲击。结果显示降解这些因子主要影响结构性染色质环，对启动子-启动子环或启动子-增强子环的影响有限，降解也不大范围改变基因表达谱。进一步，作者通过活细胞成像技术对YY1的结合动态进行了追踪，论证了YY1与DNA的结合是动态的且大部分YY1处于游离状态。进一步，作者论证了cohesin的敲除影响YY1的结合位点识别效率。本文中以下两个观点是值得注意的：1. 启动子-启动子环/启动子-增强子环与连接TAD边界的结构性染色质环的形成机理/对基因表达谱的影响是不同的；2. Cohesin敲除不仅直接破坏染色质构象，且可通过影响YY1的结合效率发挥间接作用，类似多效性机制也可能出现在其他因子上。