We have shown that loss of the chromatin remodeler Mi-2? in the basal epidermis causes rapid up-regulation of pro-inflammatory and stress response genes in the absence of any overt environmental signals or a skin barrier defect. These data support the hypothesis that immune cell regulatory genes, normally induced in the epidermis by environmental insults, are directly and actively repressed by chromatin regulators, under conditions of epidermal homeostasis. We now propose to study the chromatin-based mechanisms by which immune-regulatory genes are kept poised for expression in keratinocytes and to determine how activation of signaling pathways by mechanical or environmental insult reverses these mechanisms. In the first aim, we will establish the ?anti-inflammatory? chromatin landscape and transcription factor network that control keratinocyte homeostasis. Genome-wide approaches will be used in keratinocytes to establish the gene networks that are directly and functionally controlled by Mi-2?. The types of regulatory elements that Mi-2? associates with, and the chromatin configuration that they are in will be established. The sequence- specific DNA binding factors that functionally interact in a synergistic or antagonistic fashion with Mi-2? will be identified. Finally, the repertoire of chromatin regulators and transcription factors involved in pro-inflammatory gene regulation in a Mi-2??independent fashion will be also established. In the second aim, we will determine how environmental signals induce pro- inflammatory gene expression in keratinocytes. The effect of environmental signals on altering the activity of both chromatin regulators and transcription factors will be studied. We will first examine the cause-effect relationship between Mi-2? and the epigenetic and transcription factor makeup at the regulatory domains of its target genes. We will then test how environmental signals induce pro-inflammatory genes by altering the activities of Mi- 2? and associated chromatin regulators and transcription factors. The role of key regulatory candidates in this molecular process will be further evaluated by genetic interference studies in mouse and human keratinocytes. The outcome of these studies will allow us to probe into conserved mechanisms that contribute to human skin disease with a pro-inflammatory basis and provide new avenues for therapeutic intervention.

Public Health Relevance

Here we investigate the mechanisms by which the dermatomyocytosis-associated epigenetic regulator (Mi-2?) supports skin homeostasis by preventing the inappropriate activation of pro-inflammatory genes in keratinocytes. An in-depth understanding of this regulatory process will help design new effective therapies for skin diseases with an inflammatory basis by targeting specific activities in the epigenetic and transcriptional networks of keratinocytes.

National Institute of Health (NIH)
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Research Project (R01)
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Special Emphasis Panel (ZRG1)
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Cibotti, Ricardo
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Massachusetts General Hospital
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