Dynamic CTCF binding directly mediates interactions among cis-regulatory elements essential for hematopoiesis

Qian Qi, Li Cheng, Xing Tang, Yanghua He, Yichao Li, Tiffany Yee, Dewan Shrestha, Ruopeng Feng, Peng Xu, Xin Zhou, Shondra Pruett-Miller, Ross C. Hardison, Mitchell J. Weiss, Yong Cheng

Research output: Contribution to journalArticlepeer-review

Abstract

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. Key Points: • Dynamic CTCF-binding sites colocalize with lineage-specific transcription factors and are essential for hematopoiesis. • Dynamic CTCF-binding sites directly mediate the chromatin interactions of associated regulatory elements.

Original languageEnglish (US)
Pages (from-to)1327-1339
Number of pages13
JournalBlood
Volume137
Issue number10
DOIs
StatePublished - Mar 11 2021

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Immunology
  • Hematology
  • Cell Biology

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