Decoding the chromatin circuitry guiding stem cell fate, regeneration, and aging
What are the mechanisms that modulate chromatin state transitions during stem cell activation?
The Polycomb Repressive Complex 1 (PRC1)-dependent histone modification is dynamically regulated during the transition of hair follicle stem cells (HFSCs) from quiescence to activation—highly enriched in resting follicles and reduced in proliferating ones. This dynamic regulation is critical for preserving HFSC quiescence and long-term regenerative potential. Interestingly, extrinsic niche signals influence this distribution. However, the molecular mechanisms by which signaling pathways modulate histone modifications and reshape the chromatin landscape during the quiescence-to-activation transition remain unknown.
In the Flora Lab, we are focused on elucidating the molecular mechanisms by which extrinsic signals integrate to dictate the chromatin landscape and maintain HFSC quiescence. Understanding this regulatory network may reveal new strategies to precisely control stem cell activation in the skin and other regenerative tissues.
How does non-canonical PRC1 recruitment contribute to chromatin organization and transcriptional repression?
Polycomb Repressive Complex 1 (PRC1) is a key chromatin regulator known for its role in gene silencing and stem cell maintenance. Traditionally, PRC1 is thought to be recruited to chromatin via PRC2-mediated H3K27me3 marks. However, our preliminary work in HFSCs and the Drosophila ovary suggests that PRC1 can localize to chromatin independently of PRC2. The mechanisms underlying this non-canonical recruitment remain poorly understood.
In the Flora Lab, we aim to uncover the molecular factors and pathways that direct PRC1 to its genomic targets in the absence of PRC2. By combining both mouse and fly genetic models, chromatin profiling, and comparative analysis across different model organisms, we seek to define how PRC1 operates outside canonical Polycomb pathways and how this alternative mode of recruitment contributes to transcriptional regulation, stem cell identity, and tissue regeneration. The ultimate goal is to test whether these non-canonical recruitment mechanisms also function in human skin stem cells using ex vivo human skin explant models.
How do age-associated changes in chromatin regulators contribute to the decline in stem cell function?
Aging is accompanied by a progressive decline in stem cell function, leading to impaired tissue regeneration and homeostasis. In the skin, both hair follicle stem cells (HFSCs) and interfollicular epidermal stem cells (EpSCs) exhibit reduced self-renewal and regenerative potential with age. Our work has uncovered that the levels of repressive histone modifications diminish in aged stem cells of the mouse back skin, suggesting that chromatin dysregulation may be a driving force behind functional decline.
In the Flora Lab, we will investigate how aging alters the chromatin landscape in epithelial stem cells and identify the molecular mechanisms responsible for the loss of epigenetic control. By comparing chromatin states in young and aged HFSCs and EpSCs, and probing their functional consequences, we aim to uncover conserved epigenetic strategies that support stem cell longevity. These insights may inform interventions to restore regenerative capacity in aging tissues.