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Highly Selective Changes in Chromatin Accessibility in Response to Pro-Inflammatory and Anti-Inflammatory Stimuli

  • Author(s): Thomas, Brandon Thomas
  • Advisor(s): Kurdistani, Siavash
  • et al.
Abstract

A major challenge in understanding complex rheumatologic and inflammatory diseases has been to understand the relative contributions and influences of multiple cytokines and cell types to disease pathogenesis. Progress has been limited by our inadequate knowledge of the underlying mechanisms responsible for regulating inflammatory responses, both in circumstances of human disease, but also at a fundamental level of how transcription factors (TFs), chromatin, and diverse stimuli regulate inducible transcription in immune cells. We have utilized in-vitro models of mouse macrophage activation combined with hi-throughput sequencing in order to provide a high-resolution view of the inflammatory response. The long- term goal is to identify modes of regulation governing inducible gene expression with the expectation that the knowledge gained will provide insight into how the immune response can be manipulated in the setting of human disease. Here, we provide evidence for both broad trends governing inducible transcription as well as examples of highly specific forms of regulation occurring at individual genes. We further provide support for utilizing mouse models in relation to questions regarding human physiology, as well as address the role of Interluekin-10 in the inhibition of inducible chromatin at sites upstream of inhibited genes.

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