Our goal is to uncover the molecular processes underlying the interplay between transcription and RNA processing to understand novel layers of gene regulation that will set the path for new therapeutic strategies.
By targeting the specific isoforms and regulatory steps that go awry in individual patients, we aim to develop ASO-based therapies that bring RNA medicine closer to personalized care
Splicing feeds back to transcription
Splicing is not only a downstream consequence of transcription; it can also feed back to regulate it. We recently described a phenomenon affecting thousands of genes, in which the splicing of internal exons promotes the use of nearby promoters and increases gene expression. Evolutionary gain of internal exons is associated with the emergence of new transcription start sites nearby, and inhibiting exon splicing reduces transcription from these promoters. Yet how the splicing machinery communicates with promoters to activate transcription remains unknown.
The exon type problem
Exons are classically defined by their position within a transcript as first, internal, or last, with each type processed by distinct molecular machinery. However, we found that thousands of exons are “hybrid,” able to function as either first and internal, or internal and last exons depending on context. This flexibility challenges the fixed view of exon identity and raises key questions about how cells determine which role a hybrid exon adopts, how these exons evolved, and how their usage shifts across tissues and cell types.
Transcription regulates splicing
How gene expression is orchestrated remains a fundamental question in molecular biology, with implications for differentiation, development, disease, and evolution. Promoters not only initiate transcription but also regulate alternative splicing, determining which isoforms a gene expresses, and genetic variants within promoters can alter splicing outcomes. Yet how a non-transcribed DNA element shapes RNA processing remains unknown.
Personalized RNA Therapeutics for Rare Diseases
Rare genetic diseases affect millions of people worldwide, yet most lack effective treatments. Many are caused by mutations that disrupt RNA processing, creating aberrant isoforms or reducing expression of essential genes. Because antisense oligonucleotides (ASOs) can be designed to target any RNA sequence, they offer a path toward therapies tailored to individual patients and their specific mutations. Our lab combines genomic analysis with patient-derived cell models to design and test personalized ASOs that correct splicing defects and restore normal gene function.
RNA Therapeutics for Cancer Prevention
Most cancer therapies act only after disease has developed, but RNA therapeutics open the possibility of intervening much earlier. Many tumor suppressors produce multiple isoforms through alternative splicing, and shifting this balance toward fully functional isoforms could restore protective activity in high-risk individuals. Our lab designs splice-switching antisense oligonucleotides (ASOs) that redirect isoform expression to boost tumor suppressor function, with the goal of developing personalized, preventive strategies for carriers of hereditary cancer mutations.
RNA Therapeutics for Cancer Treatment
Cancer cells frequently hijack alternative splicing to produce isoforms that drive proliferation, survival, and resistance to therapy. Because these isoform switches are often tumor-specific, they offer a unique opportunity for precise therapeutic intervention. Our lab develops splice-switching antisense oligonucleotides (ASOs) that redirect isoform expression in cancer cells, suppressing oncogenic isoforms or restoring tumor-suppressive ones, to inhibit tumor growth and re-sensitize tumors to existing treatments.