-Author name in bold denotes the presenting author
-Asterisk * with author name denotes a Non-ASH member
Clinically Relevant Abstract denotes an abstract that is clinically relevant.

PhD Trainee denotes that this is a recommended PHD Trainee Session.

Ticketed Session denotes that this is a ticketed session.

907 Nuclear Protein DEK Governs Quiescence and Metabolic Homeostasis of Hematopoietic Stem Cells By Shaping Chromatin Accessibility

Program: Oral and Poster Abstracts
Session: 501. Hematopoietic Stem and Progenitor Biology: Poster I
Hematology Disease Topics & Pathways:
HSCs, Animal models, Biological Processes, Technology and Procedures, epigenetics, Cell Lineage, Study Population, hematopoiesis, RNA sequencing, pathways
Saturday, December 5, 2020, 7:00 AM-3:30 PM

Zhe Chen, PhD1*, Lei Li2*, Jieping Chen2* and Yu Hou, PhD3

1Department of Hematology, Southwest Hospital, Third Military Medical University (Army Medical University), chongqing, China
2Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing, China
3Department of Hematology, Southwest Hospital, Third Military Medical University (Army Medical University), CHONGQING, China

Hematopoietic stem cells (HSCs) must achieve a balance between quiescence and activation that fulfils the demands for hematopoiesis without compromising long-term maintenance of HSCs. DEK, a chromatin architectural factor, is involved in chromatin remodeling, transcriptional regulation and DNA replication, and is implicated in genetic and epigenetic regulation of gene expression. Here, we identified that DEK is a critical regulator of HSCs quiescence. Deletion of DEK in mice resulted in abnormal hematopoiesis with an obvious decreased HSC pool size (~3700 to ~1700 cells/mouse), associated with apparent reduction in the proportion of HSCs in G0 phase as compared to control HSCs (~72% to ~57%). As shown by serial bone marrow transplantation and competitive repopulation assays, deletion of DEK impaired the self-renewal capacity of HSCs. Mechanistically, deficiency of DEK in HSC altered chromatin accessibility landscape, resulting in increased transcription of activation-specific genes (including Akt1/2, Ccnb2, and Rps6) and decreased transcription of quiescence-specific genes (including p21 and Gata2), leading to excessively activated Akt-mTOR signaling and elevated metabolism of HSC. Targeting the Akt-mTOR pathway efficiently abrogated the impaired quiescence and the increased metabolism of HSC in DEK-deficient mice, and partially rescued the long-term functions of HSC. Further, DEK regulated chromatin accessibility of HSC by recruiting the co-repressor NCoR1 to repress acetylation of histone 3 at lysine 27. Collectively, our findings revealed crucial functions of DEK in HSC quiescence maintenance and disclosed a new link between chromatin remodelers, epigenetic modification, gene transcription, and HSC homeostasis.

Disclosures: No relevant conflicts of interest to declare.

*signifies non-member of ASH