Abstract:
:The regenerative capacity of hematopoietic stem cells (HSCs) is limited by the accumulation of DNA damage. Conditional mutagenesis of the histone 3 lysine 4 (H3K4) methyltransferase, Setd1a, revealed that it is required for the expression of DNA damage recognition and repair pathways in HSCs. Specific deletion of Setd1a in adult long-term (LT) HSCs is compatible with adult life and has little effect on the maintenance of phenotypic LT-HSCs in the bone marrow. However, SETD1A-deficient LT-HSCs lose their transcriptional cellular identity, accompanied by loss of their proliferative capacity and stem cell function under replicative stress in situ and after transplantation. In response to inflammatory stimulation, SETD1A protects HSCs and progenitors from activation-induced attrition in vivo. The comprehensive regulation of DNA damage responses by SETD1A in HSCs is clearly distinct from the key roles played by other epigenetic regulators, including the major leukemogenic H3K4 methyltransferase MLL1, or MLL5, indicating that HSC identity and function is supported by cooperative specificities within an epigenetic framework.
journal_name
Bloodjournal_title
Bloodauthors
Arndt K,Kranz A,Fohgrub J,Jolly A,Bledau AS,Di Virgilio M,Lesche M,Dahl A,Höfer T,Stewart AF,Waskow Cdoi
10.1182/blood-2017-09-806844subject
Has Abstractpub_date
2018-03-22 00:00:00pages
1311-1324issue
12eissn
0006-4971issn
1528-0020pii
blood-2017-09-806844journal_volume
131pub_type
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