Stem cells have the remarkable ability to undergo asymmetric mitotic divisions that produce two distinct daughter cells. One daughter maintains the stem cell properties and regenerative potency while the other differentiates to replenish specialized cell types. The ability of adult stem cells to differentiate to replace damaged tissues provides the body with an internal repair system. However, the exact mechanisms that govern how a stem cell gives rise to a terminally differentiated cell are not very well understood. Decoding the molecular mechanisms governing stem cell maintenance and differentiation holds great promise for the advancement of regenerative medicine and for developing stem cell based therapies to treat diseases such as cancers and tissue dystrophy. Polycomb Group (PcG) is a family of proteins that are known to act as transcription repressors through their ability to generate a repressive epigenetic mark - methylation of histone H3 at lysine 27 (H3K27me3). This mark is laid down by the Polycomb Repressive Complex 2 (PRC2) and the emerging picture is that PRC2 activity is required to maintain the proliferative state of stem cells by repressing the expression of differentiation genes. In the Drosophila male germline stem cell lineage, the shift from proliferation to differentiation is marked by a decrease in PRC2 protein levels, a parallel increase in the expression levels of testis-specific homologs of TBP-associated factor (tTAFs) and a decrease in H3K27me3 levels on the promoters of terminal differentiation genes. Drosophila homolog of mammalian ubiquitously transcribed tetratricopeptiderepeat gene on the X chromosome (dUTX) is the sole fly H3K27me3 demethylase. Its function as an eraser of a repressive mark and an antagonist of PcG proteins suggests a role for dUTX in the regulation of the transition from proliferation to differentiation. Moreover, mammalian UTX has been recently shown to associate with the mammalian homolog of Trx, H3K4me3 histone methyltransferase MLL2 which raises the possibility of an interaction between dUTX and TrxG proteins and possibly the tTAFs. Firm control of H3K27me3 levels is necessary to maintain the tight regulation of the proliferation-to-differentiation transition. Mutations that inactivate UTX have been linked to human cancer;therefore, the potential role of dUTX in the reversal of PcG silencing makes it a promising target in cancer therapeutics. Results from this study will have significant implications on cancer biology and regenerative medicine.

Public Health Relevance

Many human diseases arise from the mis-regulation of stem cell activities. Diseases such as infertility and tissue dystrophy arise when stem cells lose the ability to self-renew and differentiate pre-maturely. Diseases such as cancer arise from over proliferation of stem cells that are unable to differentiate into the required adult tissue. The identification of the molecular mechanisms that govern the fate of a normal stem cell will help in understanding how malfunctioning of stem cells cause human diseases and how to prevent them and will have a broad impact on stem cell biology research and regenerative medicine.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Predoctoral Individual National Research Service Award (F31)
Project #
5F31CA165781-02
Application #
8352099
Study Section
Special Emphasis Panel (ZRG1-F05-A (20))
Program Officer
Bini, Alessandra M
Project Start
2011-11-16
Project End
2014-11-15
Budget Start
2012-11-16
Budget End
2013-11-15
Support Year
2
Fiscal Year
2013
Total Cost
$42,232
Indirect Cost
Name
Johns Hopkins University
Department
Biology
Type
Schools of Arts and Sciences
DUNS #
001910777
City
Baltimore
State
MD
Country
United States
Zip Code
21218