A unified model of human hemoglobin switching through single-cell genome editing.
Journal
Nature communications
ISSN: 2041-1723
Titre abrégé: Nat Commun
Pays: England
ID NLM: 101528555
Informations de publication
Date de publication:
17 08 2021
17 08 2021
Historique:
received:
26
04
2021
accepted:
02
08
2021
entrez:
18
8
2021
pubmed:
19
8
2021
medline:
31
8
2021
Statut:
epublish
Résumé
Key mechanisms of fetal hemoglobin (HbF) regulation and switching have been elucidated through studies of human genetic variation, including mutations in the HBG1/2 promoters, deletions in the β-globin locus, and variation impacting BCL11A. While this has led to substantial insights, there has not been a unified understanding of how these distinct genetically-nominated elements, as well as other key transcription factors such as ZBTB7A, collectively interact to regulate HbF. A key limitation has been the inability to model specific genetic changes in primary isogenic human hematopoietic cells to uncover how each of these act individually and in aggregate. Here, we describe a single-cell genome editing functional assay that enables specific mutations to be recapitulated individually and in combination, providing insights into how multiple mutation-harboring functional elements collectively contribute to HbF expression. In conjunction with quantitative modeling and chromatin capture analyses, we illustrate how these genetic findings enable a comprehensive understanding of how distinct regulatory mechanisms can synergistically modulate HbF expression.
Identifiants
pubmed: 34404810
doi: 10.1038/s41467-021-25298-9
pii: 10.1038/s41467-021-25298-9
pmc: PMC8371164
doi:
Substances chimiques
BCL11A protein, human
0
Chromatin
0
DNA-Binding Proteins
0
Hemoglobins
0
Repressor Proteins
0
Transcription Factors
0
ZBTB7A protein, human
0
beta-Globins
0
Globins
9004-22-2
Fetal Hemoglobin
9034-63-3
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
4991Subventions
Organisme : NIDDK NIH HHS
ID : R56 DK125234
Pays : United States
Organisme : NHLBI NIH HHS
ID : R01 HL032259
Pays : United States
Organisme : Howard Hughes Medical Institute
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA230631
Pays : United States
Organisme : NHLBI NIH HHS
ID : R01 HL146500
Pays : United States
Organisme : NIDDK NIH HHS
ID : R01 DK103794
Pays : United States
Organisme : NIDDK NIH HHS
ID : R01 DK111430
Pays : United States
Organisme : NIDDK NIH HHS
ID : U54 DK106829
Pays : United States
Informations de copyright
© 2021. The Author(s).
Références
Cell. 2020 Sep 17;182(6):1384-1400
pubmed: 32946781
Curr Opin Hematol. 2017 May;24(3):159-166
pubmed: 28099275
Blood. 2011 Dec 1;118(23):6200-8
pubmed: 22010104
Blood. 2015 Jul 2;126(1):89-93
pubmed: 26019277
Cell. 2017 Aug 24;170(5):1028-1043.e19
pubmed: 28841410
Nucleic Acids Res. 1988 Nov 25;16(22):10635-42
pubmed: 2462713
Nat Med. 2015 Mar;21(3):221-30
pubmed: 25742458
Elife. 2017 Sep 28;6:
pubmed: 28956530
Science. 2008 Dec 19;322(5909):1839-42
pubmed: 19056937
Proc Natl Acad Sci U S A. 2008 Feb 5;105(5):1620-5
pubmed: 18245381
Cold Spring Harb Perspect Med. 2013 Jan 01;3(1):a011643
pubmed: 23209159
Cell Stem Cell. 2016 Jan 7;18(1):73-78
pubmed: 26607381
Elife. 2019 May 09;8:
pubmed: 31070582
Genes Dev. 2017 Aug 15;31(16):1704-1713
pubmed: 28916711
Science. 2013 Oct 11;342(6155):253-7
pubmed: 24115442
Nat Genet. 2021 Apr;53(4):511-520
pubmed: 33649594
Cell. 2019 Mar 7;176(6):1325-1339.e22
pubmed: 30827679
N Engl J Med. 2019 Mar 7;380(10):947-959
pubmed: 30855744
Nat Genet. 2020 Feb;52(2):138-145
pubmed: 31959994
N Engl J Med. 2011 Sep 1;365(9):807-14
pubmed: 21879898
Cell. 2012 Jun 8;149(6):1233-44
pubmed: 22682246
Trends Genet. 2020 Nov;36(11):880-891
pubmed: 32741549
Nat Biotechnol. 2020 Jul;38(7):824-844
pubmed: 32572269
Blood. 2018 Nov 1;132(18):1963-1973
pubmed: 30150205
Cell. 2018 Apr 5;173(2):430-442.e17
pubmed: 29606353
Genes Dev. 2010 Apr 15;24(8):783-98
pubmed: 20395365
Blood. 2018 Apr 26;131(17):1960-1973
pubmed: 29519807
Nat Genet. 2011 Mar 20;43(4):295-301
pubmed: 21423179
Dev Cell. 2009 Oct;17(4):527-40
pubmed: 19853566
Blood. 2019 Feb 21;133(8):852-856
pubmed: 30617196
Nucleic Acids Res. 2014 Jan;42(Database issue):D1063-9
pubmed: 24137000
J Clin Invest. 2015 Jun;125(6):2363-8
pubmed: 25938782
Nat Genet. 2018 Apr;50(4):498-503
pubmed: 29610478
Am J Hum Genet. 2016 Aug 4;99(2):253-74
pubmed: 27453576
Science. 2018 Sep 28;361(6409):1341-1345
pubmed: 30262496
Nat Rev Genet. 2020 Oct;21(10):581-596
pubmed: 32839576
Cell. 2014 Aug 14;158(4):849-860
pubmed: 25126789
Nat Genet. 2007 Oct;39(10):1197-9
pubmed: 17767159
Haematologica. 2013 Feb;98(2):305-8
pubmed: 22801970
Nat Med. 2016 Sep;22(9):987-90
pubmed: 27525524
Bioessays. 2016 Jun;38(6):578-86
pubmed: 27062178
Genome Biol. 2020 Mar 5;21(1):59
pubmed: 32138752
Cell Res. 2019 Nov;29(11):960-963
pubmed: 31467406
Science. 2016 Jan 15;351(6270):285-9
pubmed: 26816381
Mol Cancer. 2006 May 16;5:18
pubmed: 16704730
Science. 2020 Mar 13;367(6483):1198-1199
pubmed: 32165573