Date of Award
Doctor of Philosophy (PhD)
The architecture of chromatin is complex and plays a substantial role in all of the biological processes involving DNA. In particular, transcriptional activation depends on the interplay of dozens of chromatin modifiers to establish an epigenetic landscape permissive of gene transcription. Among the most dynamic histone modifications are the acetylation and methylation at histone 3 lysine 9, but the precise roles of their modifiers in conserved transcriptional programs remain unknown. Using the poly I:C-induced transcriptional response in MEFs as our model, we find that JMJD2d is a positive regulator of type I interferon responses. siRNA-depletion of the H3K9 demethylase JMJD2d attenuates gene activation and overexpression of JMJD2d potentiates the IFN response. We find that the underlying mechanism involves the activation of enhancers – knockdown of JMJD2d attenuates stimulus-induced enhancer activation, which is normally characterized by the accumulation of acetylated H3K9 and increased enhancer RNA transcription. In short, JMJD2d appears to control IFN responses by enabling the transition of enhancers from ‘poised’ (H3K9me3) to ‘active’ (H3K9ac) that allows for eRNA production. In support of this hypothesis, we observe that JMJD2d is tightly associated with enhancers in the genome and preferentially binds active enhancer regions. Taken together, JMJD2d represents the first example of a chromatin modifier with enhancer specificity and emerges as a potential therapeutic target in the modulation of IFN responses.
Chandwani, Rohit, "Stochastic Activation of Enhancers in the Innate Immune Response by the Histone Demethylase JMJD2D" (2014). Student Theses and Dissertations. 265.