Deciphering the molecular mechanisms of adult stem cell (SC) fate decisions and genome plasticity is essential for understanding disease and for tissue regenerative therapy. In embryonic stem cells (ESCs), genome plasticity is known to be associated with specialized chromatin states. In contrast, adult tissue SC plasticity is poorly understood. We use mouse hair follicle SCs as a model system to understand how chromatin states previously associated with plasticity in proliferating ESC might work in tissue SCs during prolong periods of G0 quiescence. Based on our preliminary data we hypothesize that tissue signaling directly couples two fundamental hair follicle SC characteristics for optimal skin homeostasis: G0 quiescence and genome plasticity. We suggest that this coupling is highly coordinated and occurs when adult hair follicle SCs require maximum genome flexibility, and is required to facilitate SC fate choices for the next stage of hair growth. We will test this hypothesis in 3 specific aims: (1) modulate levels of activating and repressing histone H3 methylation during adult HFSC homeostasis and examine effects on SC plasticity and hair growth; (2) characterize chromatin modifications other than histone methylation and compare nascent transcript levels with levels of steady-state mRNAs and with histone marks; and (3) examine the impact of signaling pathways previously implicated in hair cycle regulation on chromatin-associated plasticity states. This work will unravel molecular pathways that regulate plasticity in an adult tissue SC system and understand how they coordinate with the SC homeostatic cycle for proper control of adult tissue physiology.
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 transcriptional regulation and how they control plasticity of cell fate decisions in adult vertebrate stem cells.
