Recent evidence has shown that alterations in epigenetic states can alter the ability of stem cell populations to differentiate into specific cell lineages and in some circumstances lead to the de-differentiation of differentiated cell types into more pluripotent stem cells. The molecular pathways controlling such epigenetic/chromatin remodeling events are still unclear. The forkhead or Fox gene family of transcriptional regulatory factors regulate tissue specific gene transcription and are important for self-renewal and differentiation of stem/progenitor cell populations during development. We have shown that the Foxp1/2/4 subfamily of Fox factors are highly expressed in developing skin and hair follicles. Recent evidence from our lab as well as others demonstrated that Foxp1/2/4 and the related Foxp3 factor interact with chromatin remodeling complexes, including NuRD and NCoR to repress gene specific expression during cell differentiation. Evidence from our lab shows that Foxp1/2/4 interact with components of the NuRD complex, mediating transcriptional repression of important target genes in the lung and heart. Our preliminary data suggest that Foxp1/2/4-NuRD interactions have profound affects on lung development as demonstrated by defects in Foxp1-HDAC2 and Foxp2-HDAC2 compound mutant mice. These studies illustrate one of the few examples of the chromatin remodeling complex NuRD interacting with a sequence specific DNA binding transcription factor. Given these fundamental roles for Foxp1/2/4 in development of the cardiovascular and pulmonary systems, we predict that they will play a similarly critical role in regulation of hair follicle development. To explore the role of Foxp1/2/4 in skin and hair follicle development, we propose to 1) determine the roles for Foxp1/2/4 in skin and hair follicle development by deleting these genes in epidermal specific knockout mice and 2) Determine the roles for HDAC1/2 in skin and hair follicle development through in vivo loss of function analyses.
These experiments aim to uncover basic molecular mechanisms regulating development, homeostasis and stem cell function in mamamlian skin and hair follicles. The information obtained in these studies has the potential to reveal novel therpeutic targets for hair loss diseases and skin cancers.
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