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

Abstract

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.

The Mutational Landscape of Myeloid Leukaemia in Down Syndrome

“…Cell type-specific CTCF binding sites that are acquired during erythroblastic differentiation are enriched in lineage-determining transcription factors such as GATA1 and TAL1. These newly acquired CTCF sites are associated with genes involved in primitive erythrocyte differentiation, suggesting that CTCF dynamic binding might be required for the expression of erythroblastic differentiation genes [109]. The cell-type specificity in CTCF binding is also observed in AML cells.…”

“…As part of its key role in the formation of TADs [81,[104][105][106][107], CTCF has been implicated in the control of gene expression during haematopoietic development [108][109][110][111]. Specifically, CTCF is required for the normal proliferation and differentiation of erythroblasts [108][109][110].…”

“…As part of its key role in the formation of TADs [81,[104][105][106][107], CTCF has been implicated in the control of gene expression during haematopoietic development [108][109][110][111]. Specifically, CTCF is required for the normal proliferation and differentiation of erythroblasts [108][109][110]. Cell type-specific CTCF binding sites that are acquired during erythroblastic differentiation are enriched in lineage-determining transcription factors such as GATA1 and TAL1.…”

Co-Regulated Genes and Gene Clusters

“…According to a number of data, an important role in this process is played by the establishment of spatial contacts between genes that code for transcription factors. Architectural proteins, primarily CTCF [52], are involved in establishing such contacts. The binding of CTCF to recognition sites on DNA, in turn, can be modulated by specific non-coding RNAs [53].…”

“…How the spatial reconfiguration of globin gene clusters is directed is not entirely clear. There are many indications that an important role in this process is played by a change in the binding profile of CTCF, to recognition sites on DNA [52,63,64]. The interaction between CTCF binding sites is modulated by histone acetylation in the surrounding regions, which in turn is directed by erythroid-specific transcription factors, in particular GATA1 [65,66].…”