CTCF is selectively required for maintaining chromatin accessibility and gene expression in human erythropoiesis

ABSTRACT: Backgrounds：The three-dimensional chromatin niche provides a precise gene expression control of cell identity, differentiation, and disease development. CTCF is considered as the most essential transcription factor regulating chromatin architecture and gene expression. However, the genome-wide impact of CTCF on erythropoiesis has not yet been extensively investigated. Results：Here, using a state-of-the-art human erythroid progenitor cell model (HUDEP-2 and HEL cell lines), we systematically investigated the effects of acute CTCF loss by an auxin-inducible degron system on transcriptional programs, chromatin accessibility, CTCF genome occupancy, and the 3D genome architecture. By integrating multi-omics datasets, we revealed that acute CTCF loss notably disrupted genome-wide chromatin accessibility and transcription network. Importantly, we identified that over thousands of chromatin accessibility regions were decreased while only a few hundred increased regions after depletion of CTCF in both HUDEP-2 and HEL lines, suggesting the role of CTCF in maintaining the proper chromatin openness in erythroid lineage. Moreover, CTCF depletion in the erythroid context significantly disrupted TAD boundary integrity and chromatin loops while not affecting the nuclear compartmentalization. Our study also reported that hundreds of erythroid lineage-specific genes were suppressed in both immature and mature stages, including metabolism-related target genes such as GOT2 and FXN. Notably, we identified a subset of genes increased their transcriptional level after the CTCF depletion, accompanied by the decreased chromatin accessibility regions that were enriched with the GATA motif. Specifically, we identified that CTCF repressed the master transcription factor GATA2 with distal decreased chromatin regions via multiple functional studies, including CTCF occupancy profiling and CRISPR/Cas9 editing of the CTCF binding site. These results suggest a suppressive role of CTCF in gene expression in erythroid lineage specification. Conclusions：In summary, our results revealed a novel role of CTCF in regulating erythroid differentiation by maintaining its proper chromatin openness, which will undoubtedly extend our understanding of CTCF biology.

ORGANISM(S): Homo sapiens

PROVIDER: GSE282070 | GEO | 2025/01/27

REPOSITORIES: GEO