Deciphering the molecular mechanisms of adult stem cell (SC) fate decisions is essential for understanding disease and for tissue regenerative therapy. The overall goal of this proposal is to utilize hair follicles and skin as model systems to address at the molecular level the interplay of transcriptional factors and epigenetic regulation in fate choice decisions of a vertebrate adult stem cell population in its native tissue. Because hair follicle stem cells synchronously proliferate and return to quiescence in the mouse skin, this system allows mechanistic insight that is otherwise more difficult to achieve.
In Aim (1) we plan to investigate in more depth the relationship between more dormant versus more active cell subpopulations in the hair follicle stem cell niche, by characterizing their morphogenetic and self-renewal ability in cell culture and cell transplantation assays. The existence of these two kinds of cell subpopulations in stem cell niches appears to be a relatively common feature for at least several vertebrate tissues. Their interplay in maintaining tissue homeostasis is important for accurate description of stem cell behavior and fate decisions.
In Aim (2) we will examine the distribution of histone marks across the genome at two stages of stem cell activity by chromatin immuno-precipitation and sequencing, and attempt to examine a potential link between two known adult tissue stem cells features: quiescence and plasticity.
In Aim (3) we will employ two transcription factors Runx1 and Gata6 as fate acquisition regulators. We will test their potential implication in remodeling the stem cell histone epigenome via interactions with a battery of histone modifying enzymes we found expressed in the hair follicle in a relevant pattern. We will induce acute loss of Runx1 and Gata6 in mouse skin and examine the mRNA expression level of specific histone modifying enzymes in the relevant hair follicle cell populations. In addition we will perform co-immunoprecipitation or pull-down experiments to examine a potential direct protein-protein interaction between Runx1 or Gata6 and specific histone modifying enzymes. This will begin to address the mechanisms of fate acquisition in a vertebrate adult stem cell population and shed light on the interplay between transcription factors that work as master regulator in orchestrating cell fate and global remodeling of histone epigenetic marks.
A large number of diseases are due to miss-regulation of cell fate acquisition of adult tissue stem cells during their activity to maintain normal tissue homeostasis. There has been recently great promise for developing novel drug therapeutics that target specific histone modifying enzymes, some already present in clinics. This proposal seeks to utilize a versatile vertebrate model system, mouse skin and hair follicles, to gain better understanding of the interplay between histone epigenetic marks and transcription factors that control cell fate decisions in adult vertebrate stem cells.
|Wang, Alex B; Zhang, Ying V; Tumbar, Tudorita (2017) Gata6 promotes hair follicle progenitor cell renewal by genome maintenance during proliferation. EMBO J 36:61-78|
|Lee, Jayhun; Kang, Sangjo; Lilja, Karin C et al. (2016) Signalling couples hair follicle stem cell quiescence with reduced histone H3 K4/K9/K27me3 for proper tissue homeostasis. Nat Commun 7:11278|
|Lee, Song Eun; Sada, Aiko; Zhang, Meng et al. (2014) High Runx1 levels promote a reversible, more-differentiated cell state in hair-follicle stem cells during quiescence. Cell Rep 6:499-513|
|Waghmare, Sanjeev K; Tumbar, Tudorita (2013) Adult hair follicle stem cells do not retain the older DNA strands in vivo during normal tissue homeostasis. Chromosome Res 21:203-12|
|Sada, Aiko; Tumbar, Tudorita (2013) New insights into mechanisms of stem cell daughter fate determination in regenerative tissues. Int Rev Cell Mol Biol 300:1-50|
|Tumbar, Tudorita (2013) Knocking off their Sox: lineage-specific repression by Polycomb in epidermal stem cells. EMBO J 32:1970-1|
|Lee, Jayhun; Hoi, Charlene S L; Lilja, Karin C et al. (2013) Runx1 and p21 synergistically limit the extent of hair follicle stem cell quiescence in vivo. Proc Natl Acad Sci U S A 110:4634-9|
|Scheitz, Cornelia Johanna Franziska; Tumbar, Tudorita (2013) New insights into the role of Runx1 in epithelial stem cell biology and pathology. J Cell Biochem 114:985-93|
|Tumbar, Tudorita (2012) Ontogeny and Homeostasis of Adult Epithelial Skin Stem Cells. Stem Cell Rev :|
|Scheitz, Cornelia Johanna Franziska; Lee, Tae Seung; McDermitt, David James et al. (2012) Defining a tissue stem cell-driven Runx1/Stat3 signalling axis in epithelial cancer. EMBO J 31:4124-39|
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