Natalie Gilbert (Horvath Lab)

Natalie Gilbert

Type 1 interferon (IFN), is the primary antiviral cytokine that is responsible for creating a barrier for virus replication in innate immunity and educating adaptive immune responses necessary for virus clearance and long term immunity. Most of the biological activities of IFN are the result of transcriptional regulation by the heterotrimeric transcription factor complex, ISGF3, which consists of STAT1, STAT2, and IRF9. IFN binding to its receptor induces ISGF3 assembly and nuclear import, which stimulates transcription from IFN-stimulated gene promoters containing IFN-stimulated response elements. In addition to its role in antiviral immunity, IFN has been identified as an essential element of cancer cell susceptibility to ionizing radiation (IR). The reduction of tumor burden following local IR treatment depends on IFN signaling, but the mechanism by which IFN assists IR is poorly understood.

Preliminary studies in the Horvath lab have uncovered a rapid and transient genome wide alteration to chromatin accessibility in response to IFN treatment, which we refer to as Comprehensive Chromatin Reorganization (CCR). My project aims to (1) determine the mechanistic basis for CCR in IFN-treated human cell lines, (2) quantify the effects of CCR on chromatin and nuclear dynamics by direct physical measurements, and (3) map the genomic sites of IFN-induced chromatin access. These aims will will validate CCR as a fundamental consequence to IFN stimulation and test the hypothesis that CCR results in increased susceptibility to IR-induced DNA damage.

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