The Cell Type-Specific 5hmC Landscape and Dynamics of Healthy Human Hematopoiesis and TET2-Mutant Preleukemia.
Journal
Blood cancer discovery
ISSN: 2643-3249
Titre abrégé: Blood Cancer Discov
Pays: United States
ID NLM: 101764786
Informations de publication
Date de publication:
06 07 2022
06 07 2022
Historique:
received:
12
08
2021
revised:
07
02
2022
accepted:
04
05
2022
pmc-release:
06
01
2023
pubmed:
10
5
2022
medline:
8
7
2022
entrez:
9
5
2022
Statut:
ppublish
Résumé
The conversion of 5-methylcytosine (5mC) to 5-hydroxymethylcytosine (5hmC) is a key step in DNA demethylation that is mediated by ten-eleven translocation (TET) enzymes, which require ascorbate/vitamin C. Here, we report the 5hmC landscape of normal hematopoiesis and identify cell type-specific 5hmC profiles associated with active transcription and chromatin accessibility of key hematopoietic regulators. We utilized CRISPR/Cas9 to model TET2 loss-of-function mutations in primary human hematopoietic stem and progenitor cells (HSPC). Disrupted cells exhibited increased colonies in serial replating, defective erythroid/megakaryocytic differentiation, and in vivo competitive advantage and myeloid skewing coupled with reduction of 5hmC at erythroid-associated gene loci. Azacitidine and ascorbate restored 5hmC abundance and slowed or reverted the expansion of TET2-mutant clones in vivo. These results demonstrate the key role of 5hmC in normal hematopoiesis and TET2-mutant phenotypes and raise the possibility of utilizing these agents to further our understanding of preleukemia and clonal hematopoiesis. We show that 5-hydroxymethylation profiles are cell type-specific and associated with transcriptional abundance and chromatin accessibility across human hematopoiesis. TET2 loss caused aberrant growth and differentiation phenotypes and disrupted 5hmC and transcriptional landscapes. Treatment of TET2 KO HSPCs with ascorbate or azacitidine reverted 5hmC profiles and restored aberrant phenotypes. This article is highlighted in the In This Issue feature, p. 265.
Identifiants
pubmed: 35532363
pii: 696467
doi: 10.1158/2643-3230.BCD-21-0143
pmc: PMC9338760
doi:
Substances chimiques
Chromatin
0
DNA-Binding Proteins
0
Proto-Oncogene Proteins
0
Dioxygenases
EC 1.13.11.-
TET2 protein, human
EC 1.13.11.-
Azacitidine
M801H13NRU
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Research Support, N.I.H., Extramural
Langues
eng
Sous-ensembles de citation
IM
Pagination
346-367Subventions
Organisme : NCI NIH HHS
ID : R01 CA251331
Pays : United States
Organisme : NHLBI NIH HHS
ID : R01 HL142637
Pays : United States
Organisme : NIH HHS
ID : 1R01HL142637
Pays : United States
Informations de copyright
©2022 American Association for Cancer Research.
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