Journal
BLOOD
Volume 137, Issue 10, Pages 1327-1339Publisher
AMER SOC HEMATOLOGY
DOI: 10.1182/blood.2020005780
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Funding
- National Institutes of Health, National Institute of General Medical Sciences [R35GM133614]
- National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases [R24DK106766]
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The study revealed dynamic, cell-type-specific binding sites for CTCF in different types of primary blood cells, which play a critical role in blood cell development and may facilitate interactions between distal regulatory elements and target promoters.
While constitutive CCCTC-binding factor (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.
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