Keratinocytes in the skin are poised to respond to environmental insults by activating a proliferation-repair response and also by stimulating resident immune cells to initiate an inflammatory response. This is mediated by a panoply of cytokines, chemokines and stress-induced antigens expressed by keratinocytes. The rapid activation and subsequent suppression of the genes involved in this response implies that they are maintained in an epigenetic state in keratinocytes that is poised for transcription but responsive to environmental cues. Our studies with the chromatin remodeler Mi-2? in keratinocytes provide strong support for this hypothesis. Mi-2? has a very specific and central role in guarding against the inappropriate activation of a keratinocyte's stress response and repair functions by maintaining genes in these pathways in a repressed state. Among the Mi-2? targets is TSLP, best known as a "pro-inflammatory signal " in other contexts, which in contrast plays a key protective role to resolve an epigenetically induced stress response that occurs when Mi-2? function is blocked. The role of Mi-2? and TSLP in keratinocyte homeostasis is investigated by three specific aims. In the first aim, we establish the genes regulated by Mi-2? in wild type keratinocytes, as well as the network of transcription factors and epigenetic regulators that contribute to Mi-2?'s regulation of the stress- response gene signature. In the second aim, we further evaluate the hypothesis that Mi-2? functions by establishing a local chromatin environment that influences the recruitment or activity of transcription regulators at pro- inflammatory genes, such as TSLP.
In third aim, we address the role of TSLP, a select Mi-2? target, as a protective factor in stress-mediated skin pro-inflammatory responses. Taken together our studies seek to establish the regulatory nexus that connects the epigenetic, transcriptional and cellular mechanisms supporting keratinocyte homeostasis and stress responses

Public Health Relevance

Here we investigate the mechanisms by which the dermatomyocytosis-associated epigenetic regulator (Mi-2 ?) supports skin homeostasis and prevents the inappropriate activation of stress-response genes in the skin. Mi-2 ? modifies the regulatory environment of a wide range of genes in cooperation with more conventional transcription factors. We will identify these genes and the mechanisms by which Mi-2 ? controls them to understand how the normal activity of this regulator maintains healthy skin and interruption of its function unleashes an abnormal and pathological stress response. An in-depth understanding of this regulatory process in normal and challenged skin will help design new effective therapies for skin diseases with a pro-inflammatory basis.

National Institute of Health (NIH)
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
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Arthritis, Connective Tissue and Skin Study Section (ACTS)
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Cibotti, Ricardo
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Massachusetts General Hospital
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