Contact1307 Chevron Science Center
219 Parkman Avenue
Pittsburgh, PA 15260
Chemical Approaches towards Understanding Epigenetic Mechanisms in Human Biology and Disease
Organic Synthesis, Bioorganic Chemistry, Small Molecule Therapeutics, Protein Engineering, Structural Biology and ‘Chromatinomics’
Our group, comprised of graduate students, undergraduates and postdoctoral fellows, has built the foundation of a vibrant research program focused on epigenetics. Biochemically, epigenetics is a DNA sequence-independent mechanism that controls the transcriptional potential of a cell by turning genes ‘on’ and ‘off’ and allows cells to access genetic information only when ‘needed’. Cells employ a range of epigenetic mechanisms, most prominent being the covalent chemical modifications on chromatin (DNA and histone complex) such as acetylation and methylation of lysine residues in histones, and cytosine methylation in DNA. We employ a range of small molecules, peptides, proteins, nucleotides and their unnatural analogues towards functional elucidation of chromatin modifications in transcriptional programming and cellular differentiation. With the improved molecular understanding, we plan to employ our methods to edit epigenetic processes for cell fate reprograming as well as correcting aberrant gene expression in human diseases like obesity and cancer. Our interdisciplinary research spans synthetic organic chemistry, protein and oligonucleotide engineering, mechanistic biochemistry, structural and cell biology, proteomics and transcriptomics.
Exploring the Functions of Epigenetic Proteins by Unnatural Amino Acid Mutagenesis
In order to respond to fluctuating developmental and environmental cues, cells employ epigenetic machineries for rapid gene regulation by forming transient complexes with essential proteins such as transcription factors. It has remained a significant challenge to characterize these transient interacting partners in cells. We have developed a novel chemoproteomic approach termed ‘interaction-based protein profiling’ (IBPP) by introducing a photo-crosslinkable amino acid (PCAA) into the hydrophobic pocket of epigenetic proteins to crosslink and enrich transient interacting partners that are inaccessible to traditional methods. Applying IBPP, we have uncovered novel BRD4 interactome such as transcription factors, thus providing new mechanistic insights into how BRD4 reprograms gene expression in normal and cancer cells.
Probing the Epigenetic Proteins by Allele-Specific Chemical Genetics
Epigenetic processes are regulated by a wide range of proteins that modify (writers), recognize (readers) and remove (erasers) specific chemical groups (acetyl, methyl, phosphate) in the chromatin landscape with high spatiotemporal control. Interrogating the function of a specific member is of monumental challenge. We are employing allele-specific chemical genetics (also known as analogue-sensitive chemical genetics or ‘bump-hole’ approach) to break the biochemical degeneracy of the homologous proteins through protein-small molecule engineering. We have developed ‘hole-modified’ epigenetic proteins that can be selectively modulated by ‘bumped’ small molecules (activators/inhibitors). We are currently applying these engineered epigenetic machines to reprogram transcriptional activity in human cells to investigate how transcriptional network set by epigenetic regulators control complex biological processes such as the cell cycle, lineage commitment and oncogenesis.
Targeting Metabolic and Epigenetic Proteins for Precision Medicine
Biochemical link between metabolism and epigenetics is becoming increasingly clear. The essential metabolite 2-ketoglutarate (2KG), produced in the tricarboxylic acid (TCA) cycle by isocitrate dehydrogenases 1 (IDH1), serves as cofactor for >40 chromatin demethylases such as Ten-Eleven Translocation (TET), and Fat mass and obesity-associated protein FTO to regulate gene expression. Somatic mutations, overexpression and chromosomal translocation of these proteins drive multiple human conditions particularly cancer and obesity. We have initiated an active research program towards finding chemical inhibitors that selectively target the driver oncogenic mutations in these proteins to develop epigenome-based precision medicine.
- Melanoma SPORE Award, UPCI (2015-2016)
- Winters Foundation Biomedical Research Award (2014)
- CRDF Award, University of Pittsburgh (2014)
- Chair's Outstanding Poster Award, Bioorganic Gordon Conference (2011)
- Visiting Research Fellowship, Starr Cancer Consortium (2010)