TY - JOUR
T1 - Epigenomic analysis of KLF1 haploinsufficiency in primary human erythroblasts
AU - Heshusius, Steven
AU - Grech, Laura
AU - Gillemans, Nynke
AU - Brouwer, Rutger W. W.
AU - den Dekker, Xander T.
AU - van IJcken, Wilfred F. J.
AU - Nota, Benjamin
AU - Felice, Alex E.
AU - van Dijk, Thamar B.
AU - von Lindern, Marieke
AU - Borg, Joseph
AU - van den Akker, Emile
AU - Philipsen, Sjaak
N1 - Funding Information: Research in our laboratories is funded by the Landsteiner Foundation for Blood Transfusion Research (LSBR 1040 and 1627), the Netherlands Organization for Scientific Research (ZonMw-TOP 40-00812-98-12128; ZonMw-TAS 40-41400-98-1327), the Netherlands Genomics Initiative (NGI Zenith 93511036), and EU fp7 Specific Cooperation Research Project THALAMOSS (306201). Publisher Copyright: © 2022, The Author(s).
PY - 2022/12/1
Y1 - 2022/12/1
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85122863241&partnerID=8YFLogxK
U2 - https://doi.org/10.1038/s41598-021-04126-6
DO - https://doi.org/10.1038/s41598-021-04126-6
M3 - Article
C2 - 35013432
SN - 2045-2322
VL - 12
JO - Scientific reports
JF - Scientific reports
IS - 1
M1 - 336
ER -