Research Summary

Understanding the Enhancer-Code used by IFNg in the Activation/Repression of Target Genes during Inflammation

Eukaryotic gene expression is tightly controlled in a spatio-temporal manner by distal regulatory elements called as enhancers. Enhancers being highly cell type-specific, deliver crucial transcriptional machinery to the target genes by virtue of looping. Although discovered 35 years ago, enhancer functions and their mechanism of action still remains poorly understood. Yet another layer of enhancer-mediated transcriptional regulation has been uncovered by the recent discovery of ncRNA (eRNA) transcription from active enhancers, further widening the gap between the known and unknowns of enhancer-mediated gene regulation. eRNAs bear several common and unique features with lncRNAs and their expression levels are highly correlated with the activity of the functional enhancers both in developmental and signal-regulated transcription programs. In addition, enhancer alterations have been linked with defects in development and disease outcomes. Therefore, understanding enhancer functions is crucial in developing therapeutic strategies that target enhancers and eRNAs.

Using locus-specific as well as genome-wide approaches, I strive to uncover the following aspects of this conundrum: (i) How is the specificity between an enhancer and the corresponding promoter defined? (ii) Role of enhancers in setting up the three-dimensional chromatin architecture and its alterations during signaling cascades. (iii) Role of eRNAs-associated distinct protein cargos in the enhancer-mediated activation vs. repression events.

Figure Legend: Schematic depicts the functional anatomy of an enhancer-promoter unit: Functional enhancers are marked by H3k27ac and harbor binding sites for lineage and tissue-type specific transcription factors, these in turn recruit the co-factors triggering eRNA transcription from enhancer in both sense and antisense orientations. These functional enhancers physically contact promoters by bending the intervening DNA to deliver the protein complexes that are directly recruited by enhancers and/or by eRNAs. The looping is facilitated by mediator, cohesin and potentially by eRNAs.