Abstract
The expression of the human β-like globin genes follows a well-orchestrated developmental pattern, undergoing two essential switches, the first one during the first weeks of gestation (ε to γ), and the second one during the perinatal period (γ to β). The γ- to β-globin gene switching mechanism includes suppression of fetal (γ-globin, HbF) and activation of adult (β-globin, HbA) globin gene transcription. In hereditary persistence of fetal hemoglobin (HPFH), the γ-globin suppression mechanism is impaired leaving these individuals with unusual elevated levels of fetal hemoglobin (HbF) in adulthood. Recently, the transcription factors KLF1 and BCL11A have been established as master regulators of the γ- to β-globin switch. Previously, a genomic variant in the KLF1 gene, identified by linkage analysis performed on twenty-seven members of a Maltese family, was found to be associated with HPFH. However, variation in the levels of HbF among family members, and those from other reported families carrying genetic variants in KLF1, suggests additional contributors to globin switching. ASF1B was downregulated in the family members with HPFH. Here, we investigate the role of ASF1B in γ- to β-globin switching and erythropoiesis in vivo. Mouse-human interspecies ASF1B protein identity is 91.6%. By means of knockdown functional assays in human primary erythroid cultures and analysis of the erythroid lineage in Asf1b knockout mice, we provide evidence that ASF1B is a novel contributor to steady-state erythroid differentiation, and while its loss affects the balance of globin expression, it has no major role in hemoglobin switching.
Highlights
The expression of the β-like globin genes follows a wellorchestrated developmental pattern, undergoing two essential switches, the first one during the first weeks of gestation (ε to γ), and the second one around birth (γ to β)[1,2,3,4]
ASF1B is downregulated in human primary erythroid progenitors carrying the p.K288X KLF1 variant A SNP in the KLF1 gene resulting in p.K288X protein variant, causative of the inherited hereditary persistence of fetal hemoglobin (HPFH) in 10 out of 27 recruited members of a Maltese family, was reported previously [16]
Examining in more detail the region in chromosome 19 that showed the highest LOD scores and the expression in erythroid primary cultures of the neighboring genes in close proximity (GSE22109), we identified ASF1B, which was found to be downregulated in HPFH family members (Fig. 1a) [16]
Summary
The expression of the β-like globin genes follows a wellorchestrated developmental pattern, undergoing two essential switches, the first one during the first weeks of gestation (ε to γ), and the second one around birth (γ to β)[1,2,3,4]. The expression of the β-like globin genes follows a wellorchestrated developmental pattern, undergoing two essential switches, the first one during the first weeks of gestation (ε to γ), and the second one around birth (γ to β). Fetal hemoglobin (HbF), composed of two α-globin and two γ-globin chains, is the dominant type of hemoglobin during the fetal stages of development. HbF is gradually replaced by adult hemoglobin (HbA), consisting of two α-globin and two βglobin chains. Already at 6 months of age, the major hemoglobin in the circulation is HbA [5]. Residual amounts of HbF continue to be synthesized throughout adult life, and the amounts vary considerably, with the large majority of adults having less than 1% of HbF.
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