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
dc.contributor.author Chung, Jennifer E.
dc.contributor.author Magis, Wendy
dc.contributor.author Vu, Jonathan
dc.contributor.author Heo, Seok-Jin
dc.contributor.author Wartiovaara, Kirmo
dc.contributor.author Walters, Mark C.
dc.contributor.author Kurita, Ryo
dc.contributor.author Nakamura, Yukio
dc.contributor.author Boffelli, Dario
dc.contributor.author Martin, David I. K.
dc.contributor.author Corn, Jacob E.
dc.contributor.author Dewitt, Mark A.
dc.date.accessioned 2019-03-08T06:23:01Z
dc.date.available 2019-03-08T06:23:01Z
dc.date.issued 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 . https://doi.org/10.1371/journal.pone.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.identifier.uri http://hdl.handle.net/10138/299967
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.identifier.doi https://doi.org/10.1371/journal.pone.0208237
dc.type.uri info:eu-repo/semantics/other
dc.type.uri info:eu-repo/semantics/publishedVersion
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