Figure 1.
Schematic representation of the human α-globin cluster: characterization of open chromatin and chromatin interaction profiles. (A) Schematic diagrams of the α-globin locus located in the subtelomeric region of chromosome 16. The top track represents the wild-type (WT) locus (αα). The tracks beneath represent the 2 alleles inherited by the patient. For clarity, intervening genes and structural elements are not included. The paternal allele is (αα)ALT and the maternal allele is --SEA. (B) The open chromatin landscape at the α-globin locus (ATAC-seq) in primary erythroid cells on day 13 of erythroid differentiation. The top track is generated from cells derived from 3 unrelated WT controls (αα/αα), the middle is from a carrier of the SEA mutation (αα/--SEA), and the bottom is from the patient (--SEA/(αα)ALT). In the patient’s cells, marked reduction in ATAC signal is observed at the R2 enhancer and the α-globin genes. No new peaks are seen. Genes and pseudogenes are annotated below the scale bar. (C) Chromatin interaction profiles between the α-globin promoters (arrowheads) and the surrounding chromatin in primary erythroid cells (Capture-C). Peaks along the track represent interactions with the α-globin promoters. Although there are increased interactions with chromatin adjacent to the promoters due to proximity effects, in the WT setting, there is a marked increase in interactions with chromatin regions containing the enhancers, even though they lie up to 70-kb away. The top track depicts the mean interaction profile observed in cells from three unrelated WT controls (αα/αα), and the middle track is the interaction profile observed in cells taken from the patient, which shows an absence of interactions between the α-globin promoters and R2, in keeping with its deletion on that allele. The bottom track depicts the reduction in interactions when comparing the patient and the WT controls, represented as log-adjusted P values. There is a highly significant reduction in interactions between the α-globin promoters and R2 because of its deletion, and a modest reduction in interactions between the promoters and R1, R3, and R4. Intersection of the Capture-C, ATAC-seq, and dbSNP data reveals that this reduction in interactions in cis with the deleted R2 is also matched by reduced chromatin accessibility on the same allele at R3 as measured by ATAC-seq (the patient did not have any SNPs in R1 or R4 so these could not be assessed). SNP, single nucleotide polymorphism.

Schematic representation of the human α-globin cluster: characterization of open chromatin and chromatin interaction profiles. (A) Schematic diagrams of the α-globin locus located in the subtelomeric region of chromosome 16. The top track represents the wild-type (WT) locus (αα). The tracks beneath represent the 2 alleles inherited by the patient. For clarity, intervening genes and structural elements are not included. The paternal allele is (αα)ALT and the maternal allele is --SEA. (B) The open chromatin landscape at the α-globin locus (ATAC-seq) in primary erythroid cells on day 13 of erythroid differentiation. The top track is generated from cells derived from 3 unrelated WT controls (αα/αα), the middle is from a carrier of the SEA mutation (αα/--SEA), and the bottom is from the patient (--SEA/(αα)ALT). In the patient’s cells, marked reduction in ATAC signal is observed at the R2 enhancer and the α-globin genes. No new peaks are seen. Genes and pseudogenes are annotated below the scale bar. (C) Chromatin interaction profiles between the α-globin promoters (arrowheads) and the surrounding chromatin in primary erythroid cells (Capture-C). Peaks along the track represent interactions with the α-globin promoters. Although there are increased interactions with chromatin adjacent to the promoters due to proximity effects, in the WT setting, there is a marked increase in interactions with chromatin regions containing the enhancers, even though they lie up to 70-kb away. The top track depicts the mean interaction profile observed in cells from three unrelated WT controls (αα/αα), and the middle track is the interaction profile observed in cells taken from the patient, which shows an absence of interactions between the α-globin promoters and R2, in keeping with its deletion on that allele. The bottom track depicts the reduction in interactions when comparing the patient and the WT controls, represented as log-adjusted P values. There is a highly significant reduction in interactions between the α-globin promoters and R2 because of its deletion, and a modest reduction in interactions between the promoters and R1, R3, and R4. Intersection of the Capture-C, ATAC-seq, and dbSNP data reveals that this reduction in interactions in cis with the deleted R2 is also matched by reduced chromatin accessibility on the same allele at R3 as measured by ATAC-seq (the patient did not have any SNPs in R1 or R4 so these could not be assessed). SNP, single nucleotide polymorphism.

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