Mild dyserythropoiesis and β-like globin gene expression imbalance due to the loss of histone chaperone ASF1B

Human Genomics

Iris M. De Cuyper¹  Athanassia Kafasi¹  Rob van Zwieten²  Frank G. Grosveld³  Nynke Gillemans³  Sjaak Philipsen³  Petros Papadopoulos⁴  Laura Gutiérrez⁵  Celina María Benavente Cuesta⁶  Zahra Kadri⁷  George P. Patrinos⁸  Jeffrey Berghuis⁹  Martijn Veldthuis⁹  Muriel Vernet^1,10  Daniel Lewandowski^1,11  Vilma Barroca^1,11 

[1] Department of Blood Cell Research, Sanquin Research and Landsteiner Laboratory, AMC, UvA, Amsterdam, The Netherlands;Department of Blood Cell Research, Sanquin Research and Landsteiner Laboratory, AMC, UvA, Amsterdam, The Netherlands;Laboratory of Red Blood Cell Diagnostics, Sanquin Diagnostics, Amsterdam, The Netherlands;Department of Cell Biology, Erasmus MC, Rotterdam, The Netherlands;Department of Cell Biology, Erasmus MC, Rotterdam, The Netherlands;Department of Hematology, Hospital Clínico San Carlos, Instituto de Investigación Sanitaria San Carlos (IdISSC), Madrid, Spain;Department of Cell Biology, Erasmus MC, Rotterdam, The Netherlands;Department of Hematology, Hospital Clínico San Carlos, Instituto de Investigación Sanitaria San Carlos (IdISSC), Madrid, Spain;Department of Blood Cell Research, Sanquin Research and Landsteiner Laboratory, AMC, UvA, Amsterdam, The Netherlands;Platelet Research Lab -Instituto de Investigación Sanitaria del Principado de Asturias (ISPA)-, Department of Medicine -University of Oviedo-, Oviedo, Spain;Department of Hematology, Hospital Clínico San Carlos, Instituto de Investigación Sanitaria San Carlos (IdISSC), Madrid, Spain;Division of Innovative Therapies, UMR1184, Université Paris-Saclay, Inserm, CEA, Center for Immunology of Viral, Auto-immune, Hematological and Bacterial diseases (IMVA-HB/IDMIT), Fontenay-aux-Roses, France;Laboratory of Pharmacogenomics and Individualized Therapy, Department of Pharmacy, University of Patras School of Health Sciences, Patras, Greece;Department of Pathology, College of Medicine and Health Sciences and Zayed Center of Health Sciences, United Arab Emirates University, Al-Ain, United Arab Emirates;Laboratory of Red Blood Cell Diagnostics, Sanquin Diagnostics, Amsterdam, The Netherlands;UMR Stabilité Génétique Cellules Souches et Radiations, Université de Paris and Université de Paris-Saclay, CEA, 18 route du Panorama, 92260, Fontenay-aux-Roses, France;UMR Stabilité Génétique Cellules Souches et Radiations, Université de Paris and Université de Paris-Saclay, CEA, 18 route du Panorama, 92260, Fontenay-aux-Roses, France;U1274, Inserm, 18 route du Panorama, 92260, Fontenay-aux-Roses, France;

关键词: Dyserythropoiesis;    Hemoglobin switching;    Hereditary persistence of fetal hemoglobin (HPFH);    Thalassemia;    Gene expression;    Erythropoiesis;    ASF1B;    KLF1;    BCL11A;   

DOI  :  10.1186/s40246-020-00283-3

来源: Springer

【 摘 要 】

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.

【 授权许可】

CC BY