Yogesh Gupta, Ph.D.
Gupta Lab Expertise and Research Interests:
- Structural and chemical biology
- RNA modifications
- Epigenetic mechanisms
- Pediatric cancers
- Tumor viruses
- Drug discovery
Our studies seek to provide a complete and coherent picture of RNA epigenetics and chromatin remodeling processes in pediatric cancers and infectious diseases. We use X-ray crystallography, cryoEM, NMR, and phenotypic screenings to identify protein-nucleic acid complexes for targeted inhibition by small molecules.
RNA modification enzymes in cancer and infectious diseases
We are particularly interested in understanding the exact mechanisms by which different enzymes and accessory factors install, read, and remove covalent chemical modifications on RNA. N6-methyladenosine (m6A) is the most prevalent internal modification in human mRNAs. The m6A writer, reader, and eraser complexes modulate the stability of RNA transcripts, thereby affecting cellular homeostasis and disease outcomes. Due to their pro-tumorigenic roles in several cancers, they have emerged as attractive therapeutic targets. We are studying the structures and specificity of these enzymes. Our recent work on METTL3 and METTL14, the human m6A writer complex, sheds new light on its DNA-altering function and how this activity is regulated by the tight binding of structured RNA elements in human cells (eLife, 2022).
2’-O-ribose methylation (2’-O-me) is another important mRNA modification mark that regulates the host's innate immune response. Viral enzymes install this mark on their first transcribed nucleotide in mRNAs to trick and evade the host's innate immune restriction. Recently, we uncovered the structural basis of the 2’-O methylation of mRNA cap by the SARS-CoV-2 nsp16/nsp10 complex (Nature Communications, 2020) and the architectural role of divalent metal ions in orienting the mRNA for efficient 2’-O-methylation (Nature Communications, 2021). These studies provide unprecedented insights into mRNA cap modification in SARS-CoV-2. We are currently investigating the structures and functions of the RNA processing machinery of SARS-CoV-2 and other emerging viruses to better understand the biology of pathogenesis. An in-depth understanding of the mechanics of RNA modification machinery can guide the rational design of novel therapeutic modalities.
Chromatin Remodeling in Cancer
In a human cell, multi-subunit BAF (BRG1/BRM-associated factors) complexes utilize energy from ATP hydrolysis to re-organize the three-dimensional architecture of chromatin and associated factors so that regulatory DNA regions are accessible to transcription factors. Normally, the expression levels and composition of BAF complexes and transcription factors are tightly regulated to properly maintain the organization and integrity of the human genome. But in cancer cells, both assembly and recruitment of the BAF chromatin-modifying enzyme complexes are disrupted by mutations, deletions, and overexpression of individual subunits, causing aberrant or residual BAF complexes. In addition, the aggressiveness of childhood cancers is linked to chromosomal translocation events where parts of two genes are fused to form a single chimeric protein. A combination of defective BAFs and their interplay with chimeric proteins is advantageous for the proliferation and survival of several types of pediatric cancers. We are studying the structure, mechanism, and specificity of factors that we recently found critical for this system's activity and assembly. Our results will inform novel approaches to abolish the tumor-promoting functions of aberrant BAFs (Funding source, CPRIT: RP190534).
Related Diseases: Pediatric cancers, viral infections
Techniques: X-ray crystallography, CryoEM, NMR spectroscopy, small-angle X-ray scattering, phenotypic screenings, structural virology
Research & Grants
We are particularly interested in understanding the exact mechanisms by which different enzymes and accessory factors cross-talk, assemble, and install various covalent chemical modifications on both coding and noncoding RNAs. N6-methyladenosine (m6A) is human mRNAs' most prevalent form of internal post-transcriptional modifications. The m6A-associated complexes drive cellular transformation and sustained oncogenic translation in cancer. A complete structural elucidation of m6A sub-complexes would facilitate designing therapeutic strategies to selectively target the dysregulated human RNA methylome in cancer.