Project Details
Projekt
Aging of hematopoietic stem cells and the epigenetic drift: a pathway to rejuvenation.
Subject Area
Hematology, Oncology
Term
from 2015 to 2018
Project identifier
Deutsche Forschungsgemeinschaft (DFG) - Project number 279873534
Somatic stem cells are central for tissue homeostasis and loss of stem cell function contributes to tissue attrition upon aging. This age-dependent functional decline of somatic stem cells can be improved by targeted pharmacological approaches, which demonstrates that the functional decline of aged stem cells and tissues is reversible. An emerging body of evidence supports an essential role for epigenetic regulatory networks in influencing stem cell function upon aging. My recently published data demonstrate that in hematopoietic stem cells (HSCs) the level of acetylated histone 4 on lysine 16 (AcH4K16, an epigenetic mark) decreases and its localization within the nucleus is altered with age. This aging-associated change in AcH4K16 is caused by an elevated activity of the small RhoGTPase Cdc42 in aged stem cells and plays a role in the process of aging and rejuvenation of HSCs. The cellular and molecular mechanisms regarding this novel Cdc42-AcH4K16 axis are though not yet understood.The central hypothesis of the present proposal is that HSCs are endowed with a specific epigenetic signature with respect to acetylation of histone 4 as well as the spatial organization of chromatin (structural organization of chromosomes, nucleoli and chromocenters inside the nucleus). This epigenetic signature changes upon aging of HSCs, eventually influencing stem cell function by an impaired transmission of epigenetic information to daughter cells during HSC division. Cdc42 activity plays a role in this mechanism by influencing the level or/and distribution of acetylation of histone 4 and the overall chromatin organization in HSCs.Therefore, the current proposal investigates (OBJ.1) the establishment and the maintenance of a specific epigenetic signature in HSCs, (OBJ. 2) the functional impact of its alteration with age in determining mode of stem cell division and daughter cell fate commitment and (OBJ. 3) how Cdc42 activity influences the epigenetic signature in HSCs.
DFG Programme
Independent Junior Research Groups
International Connection
USA
Cooperation Partners
Professor Dr. Heinrich Leonhardt; Professor Dr. Christoph Plass; Professor Dr. Yi Zheng
