Dynamic CTCF binding directly mediates interactions among cis-regulatory elements essential for hematopoiesis.
Dynamic CTCF binding directly mediates interactions among cis-regulatory elements essential for hematopoiesis.
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DOI：
10.1182/blood.2020005780
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发表时间：
2020-12
期刊：
影响因子：
20.3
通讯作者：
Qian Qi;Li Cheng;Xing Tang;Yanghua He;Yichao Li;Tiffany Yee;Dewan Shrestha;Ruopeng Feng;Peng Xu;Xin Zhou;Shondra M. Pruett-Miller;R. Hardison;M. Weiss;Yong Cheng
中科院分区：
文献类型：
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作者：
Qian Qi;Li Cheng;Xing Tang;Yanghua He;Yichao Li;Tiffany Yee;Dewan Shrestha;Ruopeng Feng;Peng Xu;Xin Zhou;Shondra M. Pruett-Miller;R. Hardison;M. Weiss;Yong Cheng
虽然结构性的CTCF结合位点是维持染色质结构相对不变所必需的，如拓扑结合结构域，但CTCF在控制细胞类型特异性转录调控中的确切作用仍未得到很好的研究。我们检测了来自同一捐献者的不同类型原代血细胞中CTCF的占有率，以阐明CTCF在血细胞发育过程中的基因调控中的新作用。我们确定了与谱系特异性转录因子共定位的CTCF的动态、细胞类型特异性结合位点。这些动态位点富含与不同谱系中的血细胞特性相关的单核苷酸多态，并且它们与控制造血的关键调控元件相吻合。基于CRISPR/Cas9的扰动实验表明，这些动态的CTCF结合位点在红细胞发育中起着关键作用。此外，动态位点上CTCF结合基序的精确缺失取消了红系基因(如RBM38)与其相关增强子的相互作用，并导致了异常的红细胞生成。这些结果提示了CTCF的一种新的细胞类型特异性功能，在这种功能中，它可能有助于促进远端调控蛋白与目标启动子的相互作用。我们对CTCF的动态、细胞类型特异性结合和功能的研究为造血过程中的转录调控提供了新的见解。
While constitutive CTCF-binding sites are needed to maintain relatively invariant chromatin structures, such as topologically associating domains, the precise roles of CTCF to control cell type-specific transcriptional regulation remain poorly explored. We examined CTCF occupancy in different types of primary blood cells derived from the same donor to elucidate a new role for CTCF in gene regulation during blood cell development. We identified dynamic, cell type-specific binding sites for CTCF that colocalize with lineage-specific transcription factors. These dynamic sites are enriched for single nucleotide polymorphisms that are associated with blood cell traits in different linages, and they coincide with the key regulatory elements governing hematopoiesis. CRISPR/Cas9-based perturbation experiments demonstrated that these dynamic CTCF-binding sites play a critical role in red blood cell development. Furthermore, precise deletion of CTCF-binding motifs in dynamic sites abolished interactions of erythroid genes, such as RBM38, with their associated enhancers and led to abnormal erythropoiesis. These results suggest a novel, cell type-specific function for CTCF in which it may serve to facilitate interaction of distal regulatory emblements with target promoters. Our study of the dynamic, cell type-specific binding and function of CTCF provides new insights into transcriptional regulation during hematopoiesis.