Please use this identifier to cite or link to this item:
Title: Epigenomic analysis of KLF1 haploinsufficiency in primary human erythroblasts
Authors: Heshusius, Steven
Grech, Laura
Gillemans, Nynke
Brouwer, Rutger W. W.
Dekker, Xander T. den
IJcken, Wilfred F. J. van
Nota, Benjamin
Felice, Alex E.
Dijk, Thamar B. van
Lindern, Marieke von
Borg, Joseph J.
Akker, Emile van den
Philipsen, Sjaak
Keywords: Cytology
Molecular biology
Issue Date: 2022
Publisher: Nature Publishing Group
Citation: Heshusius, S., Grech, L., Gillemans, N., Brouwer, R. W., den Dekker, X. T., van IJcken, W. F., ... & Philipsen, S. (2022). Epigenomic analysis of KLF1 haploinsufficiency in primary human erythroblasts. Scientific Reports, 12(1), 1-11.
Abstract: Haploinsufficiency for the erythroid-specific transcription factor KLF1 is associated with hereditary persistence of fetal hemoglobin (HPFH). Increased HbF ameliorates the symptoms of β-hemoglobinopathies and downregulation of KLF1 activity has been proposed as a potential therapeutic strategy. However, the feasibility of this approach has been challenged by the observation that KLF1 haploinsufficient individuals with the same KLF1 variant, within the same family, display a wide range of HbF levels. This phenotypic variability is not readily explained by co-inheritance of known HbF-modulating variants in the HBB, HBS1L-MYB and/or BCL11A loci. We studied cultured erythroid progenitors obtained from Maltese individuals in which KLF1 p.K288X carriers display HbF levels ranging between 1.3 and 12.3% of total Hb. Using a combination of gene expression analysis, chromatin accessibility assays and promoter activity tests we find that variation in expression of the wildtype KLF1 allele may explain a significant part of the variability in HbF levels observed in KLF1 haploinsufficiency. Our results have general bearing on the variable penetrance of haploinsufficiency phenotypes and on conflicting interpretations of pathogenicity of variants in other transcriptional regulators such as EP300, GATA2 and RUNX1.
Appears in Collections:Scholarly Works - FacHScABS

Files in This Item:
File Description SizeFormat 
Epigenomic_analysis_of_KLF1_haploinsufficiency_in_.pdf4.43 MBAdobe PDFView/Open

Items in OAR@UM are protected by copyright, with all rights reserved, unless otherwise indicated.