Targeted therapeutic modulation of inflammatory cytokines through manipulation of noncoding RNA regulation of innate immunity in atopic dermatitis

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Atopic Dermatitis (AD), the most common chronic inflammatory skin disorder worldwide, is driven by both terminal keratinocyte differentiation defects and strong type 2 immune responses. What controls AD disease activity? Why is its response to therapy different from patient to patient? These are poorly understood problems and presents a large unmet need for both effective and safe therapeutics. In this project we seek to provide a molecular handle to explain some of these fundamental questions, by addressing a potentially under-explored source of immune regulation represented by epigenetic mechanisms. Our paradigm-shifting hypothesis centers on the epigenetic regulation of the immune response implicated in the pathogenesis of AD, and on a newly identified class of long noncoding RNAs (lncRNAs), the immune gene priming lncRNAs (IPLs), that exploit pre-formed chromatin topology at specific cytokine nuclear compartments to facilitate their epigenetic priming and activation. We propose to test and expand our hypothesis using technological advances that only now make this possible. I outline here a plan to pursue this opportunity with 3 specific aims. In Aim 1 (the R61 phase), we will establish the upstream molecular events that coordinate the epigenetic state of inflammatory genes. We hypothesize that IPLs are critical mediators that directly interact with the 3-dimensional chromatin architecture to prime chemokine promoters and enhance the pro- inflammatory responses in innate immune cell activation. We will characterize the mechanisms through which IPLs regulate IL-4 and IL-13, keystone interleukins critical to the induction and perpetuation of the Type 2 response in AD. In Aim 2, we will identity novel protein components that directly interact with the IPLs to modulate the chromatin landscape. We will also perform chromosome conformation capture across the IL-4/IL-13 locus to establish whether changing levels of IPL-IL4/13 alters chromosomal looping across the locus. Lastly, in Aim 3 (R33 phase) we will test inhibitors that specifically target IPL-4/13 in established murine AD-like models that recapitulate human AD. The IPL inhibitors will also be evaluated for their effects on the sensory responses known to influence AD behavior, to modulate direct neuronal priming by Type 2 cytokines shown to be a key step in the pathogenesis of AD. Taken together, our data will directly establish how IPLs and 3-dimensional chromatin architecture act in a cooperative manner to reduce gene-intrinsic noise, and allow robust activation of innate immune genes. A more precise fine-tuning of chemokine transcription through direct manipulations of IPL activities represents a highly valuable therapeutic strategy to achieve tailored immunomodulation in AD.