Imbalances between stem cell self-renewal versus differentiation, as well as malfunctioning of stem cell derivatives are common causes of many human diseases, including infertility and cancer. The Polycomb group (PcG) transcription repressive proteins are key regulators of both embryonic stem cells and adult stem cells. Tight control of PcG activity is critical for maintaining the balance between stem cell self-renewal/proliferation and differentiation. Down-regulation of PcG is a prerequisite for stem cells to stop self-renewal/proliferation and switch to differentiation. Consequently, enhanced PcG activities in stem/precursor cells result in cancers, such as leukemia. However, little is known about how normal expression and activity of PcG genes are regulated and how misregulation leads to disease. It is our long-term goal to apply our research results for therapeutic design to prevent infertility, cancer, and many other human diseases. The Drosophila male germline stem cell (GSC) provides an excellent in vivo model system to study stem cell identity and activity. Using this stem cell lineage, we have previously shown that the PcG proteins repress expression of terminal differentiation genes in undifferentiated cells. An orchestrated developmental program reverses the PcG silencing and turns on differentiation genes. This work uncovered an intriguing parallel between the GSC lineage and mammalian stem cell lineages. The goal of this proposal is to use this well-established stem cell system to investigate how PcG activities are tightly controlled during germ cell differentiation and how PcG proteins regulate GSC maintenance, proliferation, and differentiation. Results from our studies will have a broad impact on reproductive biology, stem cell biology, and regenerative medicine.

Public Health Relevance

Insufficient amplification of stem cells or their immediate derivatives will lead to tissue dystrophy, incapability of tissue regeneration in response to injury or aging, as well as infertility. On the other hand, uncontrolled amplification at the expense of differentiation will result in cancers. Our proposed research is addressing the central question of stem cell amplification vs. differentiation using the Drosophila male germline stem cell lineage as a model system.

National Institute of Health (NIH)
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
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Development - 1 Study Section (DEV1)
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Moss, Stuart B
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Johns Hopkins University
Schools of Arts and Sciences
United States
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Feng, Lijuan; Shi, Zhen; Xie, Jing et al. (2018) Enhancer of polycomb maintains germline activity and genome integrity in Drosophila testis. Cell Death Differ 25:1486-1502
Eun, Suk Ho; Feng, Lijuan; Cedeno-Rosario, Luis et al. (2017) Polycomb Group Gene E(z) Is Required for Spermatogonial Dedifferentiation in Drosophila Adult Testis. J Mol Biol 429:2030-2041
Feng, Lijuan; Shi, Zhen; Chen, Xin (2017) Enhancer of polycomb coordinates multiple signaling pathways to promote both cyst and germline stem cell differentiation in the Drosophila adult testis. PLoS Genet 13:e1006571
Lim, Cindy; Gandhi, Shiv; Biniossek, Martin L et al. (2015) An Aminopeptidase in the Drosophila Testicular Niche Acts in Germline Stem Cell Maintenance and Spermatogonial Dedifferentiation. Cell Rep 13:315-25
Xie, Jing; Wooten, Matthew; Tran, Vuong et al. (2015) Histone H3 Threonine Phosphorylation Regulates Asymmetric Histone Inheritance in the Drosophila Male Germline. Cell 163:920-33
Feng, Lijuan; Chen, Xin (2015) Epigenetic regulation of germ cells-remember or forget? Curr Opin Genet Dev 31:20-7
Eun, Suk Ho; Shi, Zhen; Cui, Kairong et al. (2014) A non-cell autonomous role of E(z) to prevent germ cells from turning on a somatic cell marker. Science 343:1513-6
Chepelev, Iouri; Chen, Xin (2013) Alternative splicing switching in stem cell lineages. Front Biol (Beijing) 8:50-59
Eun, Suk Ho; Stoiber, Patrick M; Wright, Heather J et al. (2013) MicroRNAs downregulate Bag of marbles to ensure proper terminal differentiation in the Drosophila male germline. Development 140:23-30
Tarayrah, Lama; Herz, Hans-Martin; Shilatifard, Ali et al. (2013) Histone demethylase dUTX antagonizes JAK-STAT signaling to maintain proper gene expression and architecture of the Drosophila testis niche. Development 140:1014-23

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