CRISPR-Cas9 interrogation of a putative fetal globin repressor in human erythroid cells

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dc.contributor University of Helsinki, Centre of Excellence in Stem Cell Metabolism en Chung, Jennifer E. Magis, Wendy Vu, Jonathan Heo, Seok-Jin Wartiovaara, Kirmo Walters, Mark C. Kurita, Ryo Nakamura, Yukio Boffelli, Dario Martin, David I. K. Corn, Jacob E. Dewitt, Mark A. 2019-03-08T06:23:01Z 2019-03-08T06:23:01Z 2019-01-15
dc.identifier.citation Chung , J E , Magis , W , Vu , J , Heo , S-J , Wartiovaara , K , Walters , M C , Kurita , R , Nakamura , Y , Boffelli , D , Martin , D I K , Corn , J E & Dewitt , M A 2019 , ' CRISPR-Cas9 interrogation of a putative fetal globin repressor in human erythroid cells ' , PLoS One , vol. 14 , no. 1 , 0208237 . en
dc.identifier.issn 1932-6203
dc.identifier.other PURE: 122113547
dc.identifier.other PURE UUID: 1a188390-bdba-4712-ba17-df112333eb0d
dc.identifier.other WOS: 000455810200005
dc.identifier.other Scopus: 85060031096
dc.description.abstract Sickle Cell Disease and beta-thalassemia, which are caused by defective or deficient adult beta-globin (HBB) respectively, are the most common serious genetic blood diseases in the world. Persistent expression of the fetal beta-like globin, also known gamma-globin, can ameliorate both disorders by serving in place of the adult beta-globin as a part of the fetal hemoglobin tetramer (HbF). Here we use CRISPR-Cas9 gene editing to explore a potential gamma-globin silencer region upstream of the delta-globin gene identified by comparison of naturally-occurring deletion mutations associated with up-regulated gamma-globin. We find that deletion of a 1.7 kb consensus element or select 350 bp sub-regions from bulk populations of cells increases levels of HbF. Screening of individual sgRNAs in one sub-region revealed three single guides that caused increases gamma-globin expression. Deletion of the 1.7 kb region in HUDEP-2 clonal sublines, and in colonies derived from CD34+ hematopoietic stem/progenitor cells (HSPCs), does not cause significant up-regulation of gamma-globin. These data suggest that the 1.7 kb region is not an autonomous gamma-globin silencer, and thus by itself is not a suitable therapeutic target for gene editing treatment of beta-hemoglobinopathies. en
dc.format.extent 17
dc.language.iso eng
dc.relation.ispartof PLoS One
dc.rights en
dc.subject HEMOGLOBIN en
dc.subject DISEASE en
dc.subject GENE en
dc.subject LIFE en
dc.subject 3111 Biomedicine en
dc.title CRISPR-Cas9 interrogation of a putative fetal globin repressor in human erythroid cells en
dc.type Article
dc.description.version Peer reviewed
dc.type.uri info:eu-repo/semantics/other
dc.type.uri info:eu-repo/semantics/publishedVersion

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