The hematopoietic regulator TAL1 is required for chromatin looping between the β-globin LCR and human γ-globin genes to activate transcription

TAL1 is a key hematopoietic transcription factor that binds to regulatory regions of a large cohort of erythroid genes as part of a complex with GATA-1, LMO2 and Ldb1. The complex mediates long-range interaction between the beta-globin locus control region (LCR) and active globin genes, and although TAL1 is one of the two DNA-binding complex members, its role is unclear. To explore the role of TAL1 in transcription activation of the human gamma-globin genes, we reduced the expression of TAL1 in erythroid K562 cells using lentiviral short hairpin RNA, compromising its association in the beta-globin locus. In the TAL1 knockdown cells, the gamma-globin transcription was reduced to 35% and chromatin looping of the (G)gamma-globin gene with the LCR was disrupted with decreased occupancy of the complex member Ldb1 and LMO2 in the locus. However, GATA-1 binding, DNase I hypersensitive site formation and several histone modifications were largely maintained across the beta-globin locus. In addition, overexpression of TAL1 increased the gamma-globin transcription and increased interaction frequency between the (G)gamma-globin gene and LCR. These results indicate that TAL1 plays a critical role in chromatin loop formation between the gamma-globin genes and LCR, which is a critical step for the transcription of the gamma-globin genes.