Mild dyserythropoiesis and beta-like globin gene expression imbalance due to the loss of histone chaperone ASF1B
Human Genomics , Volume 14 - Issue 1
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.
|Dyserythropoiesis, Hemoglobin switching, Hereditary persistence of fetal hemoglobin (HPFH), Thalassemia, Gene expression, Erythropoiesis, ASF1B, KLF1, BCL11A|
|Organisation||Biophysical Genomics, Department Cell Biology & Genetics|
Papadopoulos, P, Kafasi, A., de Cuyper, I.M, Barroca, V, Lewandowski, D, Kadri, Z., … Patrinos, GP. (2020). Mild dyserythropoiesis and beta-like globin gene expression imbalance due to the loss of histone chaperone ASF1B. Human Genomics, 14(1). doi:10.1186/s40246-020-00283-3