Abstract
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 β-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 γ-globin genes, we reduced the expression of TAL1 in erythroid K562 cells using lentiviral short hairpin RNA, compromising its association in the β-globin locus. In the TAL1 knockdown cells, the γ-globin transcription was reduced to 35% and chromatin looping of the Gγ-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 β-globin locus. In addition, overexpression of TAL1 increased the γ-globin transcription and increased interaction frequency between the Gγ-globin gene and LCR. These results indicate that TAL1 plays a critical role in chromatin loop formation between the γ-globin genes and LCR, which is a critical step for the transcription of the γ-globin genes.
Highlights
The b-globin locus adopts a specific chromatin structure in erythroid cells where the globin genes are highly transcribed
GATA-1 and NF-E2 are both required for chromatin loop formation between the locus control region (LCR) hypersensitive sites (HSs) and active Gg-globin gene in human erythroid K562 cells [6], a study using knockout mice shows that NF-E2 is dispensable for LCR/ b-globin loop formation in this context, likely because of the availability of compensatory factors [10]
TAL1 protein was reduced in the knockdown cells as shown by western blot, but GATA-1 and NF-E2 protein levels were unaffected by the knockdown (Figure 1B)
Summary
The b-globin locus adopts a specific chromatin structure in erythroid cells where the globin genes are highly transcribed. DNase I hypersensitive sites (HSs) are formed in the upstream locus control region (LCR), and histone modifications associated with active chromatin, such as H3 acetylation and H3K4 methylation, are established in the LCR and transcribed globin genes [1]. The formation of the active b-globin locus structure requires erythroid-specific transcription activators that bind to the LCR HSs and gene promoters and associate with co-activators to modify chromatin structure. GATA-1 and NF-E2 are both required for chromatin loop formation between the LCR HSs and active Gg-globin gene in human erythroid K562 cells [6], a study using knockout mice shows that NF-E2 is dispensable for LCR/ b-globin loop formation in this context, likely because of the availability of compensatory factors [10]
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