Epigenetic control of target gene activity by hairless in skin homeostasis

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DESCRIPTION (provided by applicant): The Candidate for this K01 award, Dr. Liang Liu, joined the Department of Dermatology at Columbia University in July, 2010 as an Associate Research Scientist, where he studies epigenetic regulation of epidermal development and homeostasis under the direction of Dr. Angela Christiano, the Mentor of this K01 award. Dr. Liu's research interest centers on elucidating how genes and environment interact to influence development and disease susceptibility. The major goal of this project is to define the genetic and epigenetic pathways by which HR regulates epidermal growth and proliferation in skin homeostasis. Dr. Liu is committed to a biomedical research career. During the first two years of the award, he will focus on building up his research publication record and improving his skills in scientific writing including research articles and grant applications. From the third year of this K01 award, Dr. Liu will actively seek long-term funding support that will allow him to become a fully independent investigator after completion of this K01 award. Dr. Liu's long term career goal is to establish an innovative and independent research program in cutaneous biology. Institutional Environment Columbia University is one of the top research institutions in the US and has outstanding resources for trainees. There are state of the art laboratories for work in basic and clinical research and outstanding core facilities for supporting molecular and clinical research activities. The candidate's more immediate research environment is the Department of Dermatology and the Columbia University Skin Disease Research Center. He is also a member of the NIEHS Center for Environmental Health in Northern Manhattan, which provides additional resources and infrastructure that will facilitate the completion of this project. Research Summary Hairless (HR) belongs to the Jumonji C family of proteins, many of which function as histone demethylases (HDM) that participate in gene regulation via epigenetic mechanisms. We previously reported that mutations in HR are deleterious for skin homeostasis and hair follicle cycling, as exemplified by the clinical manifestations of patients with alopecia with papular lesions. We now have compelling evidence showing that HR is a HDM, regulating a subset of target genes through histone demethylation. We hypothesize that hairless acts as an epigenetic regulator of skin homeostasis via its downstream target genes to control cell proliferation and apoptosis. To test this hypothesis, we will focus on studying the role of hairless and its downstream target genes and pathways in epidermal growth and differentiation. We will employ molecular biological methods such as gene expression profiling, ChIP-Seq analysis, and comprehensive functional assays to rigorously test our hypothesis. Findings from this project will significantly enhance our understandings of the mechanisms underlying the pathophysiology of skin disorders such as hyperplasia and photoaging. The Candidate anticipates being able to complete the studies within a five-year award period through collaborative efforts with his Mentors and collaborators.