Understanding the molecular mechanisms of gene regulation in cancer.
Our laboratory focuses on understanding the complex interplay between epigenetic modifications and aberrant alternative pre-mRNA splicing in tumorigenesis.
We employ cutting-edge molecular biology techniques, bioinformatics pipelines, and functional genomic screens to uncover novel therapeutic targets for cancer treatment.
We utilize high-throughput pooled shRNA and CRISPR/Cas9 screening to identify novel regulators of cancer-specific splicing and metabolic reprogramming. Through pooled shRNA screening, we identified SRSF9 as a key regulator linking BNIP3 splicing to autophagy in breast cancer. We also employ loss-of-function CRISPR/Cas9 approaches to dissect gene regulatory networks in tumorigenesis.
Alternative splicing process can generate multiple protein coding isoforms and is the major source of transcriptome and proteome diversity. Aberrant spliced isoforms has been implicated in various cancers. Similarly deregulation of epigenetic modifications is also associated in the development and progression of many cancers. Here, our focus is to study the role of DNA methylation and DNA binding proteins in the regulation of PKM alternative splicing in breast cancer.
Several studies have identified a change in epigenetic marks such as DNA methylation, histone modification, alterations in nucleosome remodeling, differential expression of miRNA, as well as altered expression of chromatin-modifying proteins in oral cancer. These epigenetic changes may lead to alteration in global gene expression pattern, which may attribute to the development and progression of oral cancers. We are investigating the deregulated expression of epigenetic modifiers in oral cancer to understand the role of epigenetic events in cellular transformation.
Nutraceuticals are natural products with nutrient value, reported to affect epigenetic modifiers, and have substantial therapeutic effects on cancer. In this study, we investigate the use of epigenetic-based therapeutic compounds with minimal toxicity and side effects (nutraceuticals) on cancer-specific alternative spliced isoform.
We employ large-scale genomic and transcriptomic approaches including RNA-Seq, ChIP-Seq, and integrated multi-omics analyses to identify key molecular drivers in cancer. Our work on KDM1A identified its role in cell proliferation via modulating E2F signaling through integrated genomic analyses, and we use computational pipelines to correlate intragenic DNA methylation changes with alternative splicing events across cancer types.
Hypoxia-induced response plays a key role in the progression of Triple-negative breast cancer (TNBC) and is considered as one of the hallmarks of TNBC. Hypoxia promotes an adaptive transcription response resulting in epigenetic changes which support cancer cell growth. The epigenetic modifications are known to regulate alternative splicing, which is an emerging hallmark of cancer. However, the interplay between hypoxia and alternative splicing is largely unexplored in TNBC. Here, we want to investigate whether and how hypoxia contributes to the generation of cancer-specific spliced isoforms via epigenetic modifications and whether hypoxia-induced alternative splicing is involved in the tumorigenesis of TNBC.
Exosomes are small (~30-100nm) extracellular vesicles that are derived from multivesicular endosomes and contain a variety of bioactive molecules such as DNA, mRNA, miRNA, lncRNA, proteins, and lipids. They serve as a powerful mechanism of intercellular communication. We are investigating the role of exosomes in glioblastoma progression, the most common primary CNS tumor characterized by its aggressive and malignant nature.
We investigate how 3D chromatin organization, including CTCF-mediated chromatin looping, regulates gene expression and alternative splicing in cancer. Our recent work revealed that hypoxia-induced CTCF mediates alternative splicing by coupling chromatin looping with RNA Pol II pausing to promote epithelial-mesenchymal transition (EMT) in breast cancer, integrating Hi-C and genomic datasets to map regulatory interactions.
Our lab investigates the metabolic reprogramming in cancer, particularly the Warburg effect driven by alternative splicing of metabolic enzymes like PKM2 and PFKFB3. We study how oncometabolites such as lactate orchestrate histone lactylation and c-Myc expression to enhance cancer progression. Our work integrates bioinformatics analyses of chromatin states with metabolic profiling to understand how epigenetic and metabolic pathways converge in tumorigenesis.
Autophagy is a self-regulatory catabolic process that maintains cellular integrity and concomitantly eradicates toxic molecules such as intracellular pathogens, misfolded proteins, cancerous molecules, and damaged organelles. Cancer cells have evolved by exploiting the autophagy process to fulfill energy requirements and to escape stressful conditions. Biological factors regulating autophagy provide new insight into modulating cancer progression.
90% of human genes undergo alternative splicing
CTCF promotes RNA Pol II pause for exon inclusion
DNA methylation inhibits CTCF binding at alternative exons
Aberrant splicing of PKM, VEGFA, BNIP3, MENA drives tumorigenesis
Hypoxia rewires the cancer transcriptome via epigenetic modifications
PRMT5 regulates TCF3 splicing under hypoxia to promote EMT
Our research revealed that CTCF, a DNA-binding protein, creates a "roadblock" that pauses RNA Polymerase II. This pause gives the splicing machinery enough time to recognize and include alternative exons.
When DNA methylation prevents CTCF binding, Pol II speeds through, causing exon skipping—a mechanism that can lead to cancer when it affects tumor suppressor genes.
Key molecular players studied across our research projects.
Creates Pol II roadblock for exon inclusion; binding blocked by DNA methylation.
Regulates cancer-specific splicing of BNIP3 and PKM in breast cancer.
Identified via shRNA screen as regulator of BNIP3 splicing and autophagy.
Loss under hypoxia alters DNA methylation leading to aberrant VEGFA splicing.
ERK1/2-EGR1-SRSF10 axis mediates alternative splicing in head and neck cancer.
Regulates TCF3 splicing under hypoxia to promote EMT and invasion.
HDAC6-mediated deacetylation of PTBP1 regulates PKM splicing.
Hypoxia-induced TGFβ-RBFOX2-ESRP1 axis regulates MENA splicing and EMT.
Modulates E2F signaling and cell proliferation in oral cancer.
Read our peer-reviewed papers on alternative splicing, epigenetics, and cancer biology in high-impact journals.
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