Only a small number of cells in adult tissues (the stem cells) possess the ability to self-renew at every cell division, while producing differentiating daughter cells to maintain tissue homeostasis for an organism's lifetime. A better understanding of stem cells biology will not only reveal the crucial molecular mechanisms that control the formation and maintenance of tissues but will also influence stem cell-based therapies in regenerative medicine and cancer treatments. Much progress has been made in recent years in understanding the molecular mechanisms underlying intrinsic and extrinsic controls of GSC regulation but the complex network of genetic and epigenetic pathways is only partially understood. Heterochromatin Protein 1 (HP1) is a dynamic epigenetic determinant mainly involved in heterochromatin formation, epigenetic gene silencing and telomere maintenance. Importantly, I found that, in Drosophila, HP1 plays a crucial role in the control of GSC homeostasis in female germline. My proposal is focused to understand the molecular mechanism of HP1 function in self-renewal and differentiation of adult stem cells in Drosophila melanogaster.
Stem cells are undifferentiated cells defined by their unique capacity to maintain self-renewing potential at every cell division, while producing differentiating daughter cells to ensure the correct development and to maintain tissues homeostasis (Lin et al., 2002; Spradling et al., 2001; Morrison & Spradling, 2008). A better understanding of stem cells biology will not only reveal the crucial molecular mechanisms that control the formation and maintenance of tissues, but will also influence stem cell-based therapies in regenerative medicine (Fuchs et al., 2004; Spradling et al., 2001; see Mahla RS, 2016 for review) and cancer treatments (see Shah K, 2016 for review). In view of this, deepening the molecular mechanisms that control the fine balance between stem cell self-renewal and differentiation represents one of the fundamental goals of stem cell biology. This balance often depends on the coordinated regulation of complex transcriptional and post-transcriptional hierarchies. A fast growing body of experimental evidence provides strong evidences that epigenetic mechanisms involving chromatin architecture and histone modification are very important for the regulation of stem cells maintenance and differentiation in Drosophila and mammals (Tollervey and Lunyak, 2012; Avgustinova and Benitah, 2016). However, the epigenetic regulation of adult stem cell function remains poorly defined. The Drosophila germline stem cells (GSCs) have been widely used as in vivo model system for investigating the regulatory mechanisms governing adult stem cell fate and behavior. The results of our experiments will give an important contribution to understanding the fundamental mechanisms which control the identity and maintenance of adult stem cells and certainly add a new dimension to our understanding of HP1 targeting and functions in epigenetic regulation of GSC behavior.
References
Abe et al. (2011) Biol Reprod 85, 1013-1024.
Amero et al. (1991) Genes Dev. 5, 188- 200.
Brown et al. (2010) Epigenetics Chromatin 3, 9.
Cortes et al. (1999) EMBO J 18, 3820-3833.
Decotto & Spradling (2005) Dev. Cell 9, 501-510.
De Lucia et al. (2005) Nucleic Acids Res 33, 2852-2858.
Eissenberg et al. (1990) Proc Natl Acad Sci U S A 87, 9923-9927.
Fanti et al. (1998) Mol Cell 2, 527-538.
Fuchs & Whartenby (2004) Curr Opin Mol Ther 6, 48-53.
Haynes et al. (1991) Nucleic Acids Res 19, 25-31.
James & Elgin (1986) Mol Cell Biol 6, 3862-3872.
James et al. (1989) Eur J Cell Biol 50, 170-180.
Kirilly et al. (2011) Development, 138, 5087-5097.
Kwon et al. (2010) Genes Dev 24, 2133-2145.
Lin (2002) Nature rev genet. 3(12), 931-940.
Lin et al. (2008) Mol Cell 32, 696-706.
Mahla (2016) Int J Cell Biol 2016, 6940283.
Margolis & Spradling (1995) Development 121, 3797-3807.
Perrini et al. (2004) Mol Cell 15, 467-476.
Piacentini et al. (2003) J Cell Biol 161, 707-714.
Piacentini et al. (2009) PLoS Genet 5, e1000670.
Shah (2016) Neuro Oncol 18, 1066-1078.
Spradling (1993) Cell 72, 649-651.
Spradling et al. (2011) Cold Spring Harb Perspect Biol. 3: a002642.
Spradling et al. (2001) Nature 414, 98-104.
Spradling et al. (2008) Cold Spring Harbor Symp. Quant Biol. 73, 49-57.
Vakoc et al. (2005) Mol Cell 19, 381-391.
Xie et al. (2008) Cold Spring Harb Symp Quant Biol. 73, 39¿47.
Xing & Li (2015) Sci Rep 5, 17463.
Zeng et al. (2013) J Cell Biol 201, 409-425.