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dc.contributor.authorHeshusius, Steven-
dc.contributor.authorGrech, Laura-
dc.contributor.authorGillemans, Nynke-
dc.contributor.authorBrouwer, Rutger W. W.-
dc.contributor.authorDekker, Xander T. den-
dc.contributor.authorIJcken, Wilfred F. J. van-
dc.contributor.authorNota, Benjamin-
dc.contributor.authorFelice, Alex E.-
dc.contributor.authorDijk, Thamar B. van-
dc.contributor.authorLindern, Marieke von-
dc.contributor.authorBorg, Joseph J.-
dc.contributor.authorAkker, Emile van den-
dc.contributor.authorPhilipsen, Sjaak-
dc.identifier.citationHeshusius, 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.en_GB
dc.description.abstractHaploinsufficiency 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.en_GB
dc.publisherNature Publishing Groupen_GB
dc.subjectMolecular biologyen_GB
dc.titleEpigenomic analysis of KLF1 haploinsufficiency in primary human erythroblastsen_GB
dc.rights.holderThe copyright of this work belongs to the author(s)/publisher. The rights of this work are as defined by the appropriate Copyright Legislation or as modified by any successive legislation. Users may access this work and can make use of the information contained in accordance with the Copyright Legislation provided that the author must be properly acknowledged. Further distribution or reproduction in any format is prohibited without the prior permission of the copyright holderen_GB
dc.publication.titleScientific Reportsen_GB
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