Haploinsufficiency for the erythroid transcription factor KLF1 causes hereditary persistence of fetal hemoglobin

Borg, Joseph; Papadopoulos, Petros; Georgitsi, Marianthi; Gutiérrez, Laura; Grech, Godfrey; Fanis, Pavlos; Phylactides, Marios; Verkerk, Annemieke J.M.H.; Spek, Peter J. van der; Scerri, Christian; Cassar, Wilhelmina; Galdies, Ruth; IJcken, Wilfred F. J. van; Özgür, Zeliha; Gillemans, Nynke; Hou, Jun; Bugeja, Marisa; Grosveld, Frank; Lindern, Marieke von; Felice, Alex E.; Patrinos, George P.; Philipsen, Sjaak

doi:10.1038/ng.630

Cited by 348 publications

(398 citation statements)

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“…KLF1 (or EKLF) is a critical erythroid regulator required for adult β-globin transcription (11). Recently it was shown that KLF1 occupies the BCL11A promoter and activates its expression (12,13). Consistent with previous analysis, knockdown of BCL11A or KLF1 results in marked increase in γ-globin expression and serves as positive controls for the RNAi screen.…”

Section: Bcl11a-interacting Partner Proteins In Erythroid Cellssupporting

confidence: 68%

Corepressor-dependent silencing of fetal hemoglobin expression by BCL11A

Bauer

Kerényi

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

202

188

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Reactivation of fetal hemoglobin (HbF) in adults ameliorates the severity of the common β-globin disorders. The transcription factor BCL11A is a critical modulator of hemoglobin switching and HbF silencing, yet the molecular mechanism through which BCL11A coordinates the developmental switch is incompletely understood. Particularly, the identities of BCL11A cooperating protein complexes and their roles in HbF expression and erythroid development remain largely unknown. Here we determine the interacting partner proteins of BCL11A in erythroid cells by a proteomic screen. BCL11A is found within multiprotein complexes consisting of erythroid transcription factors, transcriptional corepressors, and chromatinmodifying enzymes. We show that the lysine-specific demethylase 1 and repressor element-1 silencing transcription factor corepressor 1 (LSD1/CoREST) histone demethylase complex interacts with BCL11A and is required for full developmental silencing of mouse embryonic β-like globin genes and human γ-globin genes in adult erythroid cells in vivo. In addition, LSD1 is essential for normal erythroid development. Furthermore, the DNA methyltransferase 1 (DNMT1) is identified as a BCL11A-associated protein in the proteomic screen. DNMT1 is required to maintain HbF silencing in primary human adult erythroid cells. DNMT1 haploinsufficiency combined with BCL11A deficiency further enhances γ-globin expression in adult animals. Our findings provide important insights into the mechanistic roles of BCL11A in HbF silencing and clues for therapeutic targeting of BCL11A in β-hemoglobinopathies.gene regulation | globin switching | hematopoiesis

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Section: Bcl11a-interacting Partner Proteins In Erythroid Cellssupporting

confidence: 68%

Corepressor-dependent silencing of fetal hemoglobin expression by BCL11A

Bauer

Kerényi

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

202

188

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“…49 In humans, haploinsufficiency for KLF1 causes hereditary persistence of fetal hemoglobin. 50 In erythrocyte progenitor cells, KLF1 was upregulated 28-fold when compared with hematopoietic stem cells. 22 ALDH8A1 converts 9-cis-retinaldehyde into the 9-cis-retinoic acid, which influences hematopoiesis in the fetal liver.…”

Section: Genetic Loci Influencing Red Blood Cell Traitsmentioning

confidence: 99%

Genetic Loci Implicated in Erythroid Differentiation and Cell Cycle Regulation Are Associated With Red Blood Cell Traits

Ding

Shameer

Jouni

et al. 2012

Mayo Clinic Proceedings

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Objective: To identify common genetic variants influencing red blood cell (RBC) traits. Patients and Methods: We performed a genomewide association study from June 2008 through July 2011 of hemoglobin, hematocrit, RBC count, mean corpuscular volume, mean corpuscular hemoglobin, and mean corpuscular hemoglobin concentration in 12,486 patients of European ancestry from the electronic MEdical Records and Genomics (eMERGE) network. We developed an electronic medical record-based algorithm that included individuals who had RBC measurements obtained for clinical care and excluded values measured in the setting of hematopoietic disorders, comorbid conditions, or medications known to affect RBC production or a recent history of blood loss. Results: We identified 4 new genetic loci and replicated 11 loci previously reported to be associated with one or more RBC traits in individuals of European ancestry. Notably, genes present in 3 of the 4 newly identified loci (THRB, PTPLAD1, CDT1) and in 6 of the 11 replicated loci (KLF1, ALDH8A1, CCND3, SPTA1, FBXO7, TFR2/EPO) are implicated in erythroid differentiation and regulation of cell cycle in hematopoietic stem cells. Conclusion: Genes in the erythroid differentiation and cell cycle regulation pathways influence interindividual variation in RBC indices. Our results provide insights into the molecular basis underlying variation in RBC traits.

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“…The BCL11A locus is represented by SNP rs11886868, where the high-HbF (and protective) allele is 'C' in all populations studied so far (22,(25)(26)(27). In the Colombian samples, the two alleles have a nearly equal frequency (T=0.492 and C=0.508) (table 2).…”

Section: Resultsmentioning

confidence: 99%