Thomas Gonatopoulos-Pournatzis, Ph.D.

Aim 1: Identify and Characterize Phenotypically Relevant Alternatively Spliced Exons

A primary objective of our research is to systematically identify and characterize alternative exons with significant phenotypic roles. Aberrant splicing is recognized as a hallmark of cancer. By developing and leveraging innovative functional genomics platforms, including orthogonal exon deletion and splice site mutation strategies, we dissect the functional relevance of alternative exons at a genome-wide scale. We have identified numerous alternative exons that influence cell fitness and proliferation. Our team aims to highlight specific exons whose deletion creates vulnerabilities in cancer cells. Additionally, we are advancing exon deletion screening technology, aiming to integrate these platforms with high-content phenotypic readouts enabled by recent advances in single-cell analytics.

Aim 2: Map Novel Regulatory Networks that Control Alternative Splicing

While substantial strides have been made in deciphering the fundamental mechanisms of splicing, the intricate regulatory factors and pathways governing many alternative splicing choices remain inadequately characterized, especially in disease-state. Our approach integrates functional genomics tools, transcriptomics, computational analyses, biochemical methodologies, and animal models to delineate novel splicing regulatory factors and mechanisms and elucidate their in vivo significance and functional implications.

Relevance to cancer

Cancer cells exhibit widespread alterations in alternative splicing patterns. While substantial progress has been made in documenting these changes, identifying the downstream events responsible for disease development and progression often remains contentious. Our developed exon-resolution functional genomics strategies offer promising solutions to address this significant challenge in biomedical research.

Dr. Gonatopoulos-Pournatzis earned his Bachelor's degree in Biology from the National and Kapodistrian University of Athens, Greece, in 2007, followed by a Master's degree from King's College London in 2008. He completed his Ph.D. in 2013 at the University of Dundee, Scotland, where he conducted research in Prof. Victoria Cowling's laboratory, focusing on the mechanisms underlying mRNA cap methylation and gene expression. For his postdoctoral studies, Dr. Gonatopoulos-Pournatzis joined Prof. Ben Blencowe's laboratory at the University of Toronto, Canada, where he explored the role of alternative splicing in neurons. His work was supported by prestigious fellowships from the European Molecular Biology Organization (EMBO), Canadian Institutes of Health Research (CIHR), and the Ontario Institute of Regenerative Medicine (OIRM). In 2020, Dr. Gonatopoulos-Pournatzis established the Functional Transcriptomics Section at the RNA Biology Laboratory of the National Cancer Institute (NIH). His research group integrates functional genomics and RNA biology to systematically investigate the regulation and function of alternative splicing programs in health and disease. Dr. Gonatopoulos-Pournatzis has received several honors, including the Baxter Prize (2012), the Donnelly Centre Research Excellence Award (2018), and the NIH Distinguished Scholar Program Award (2020).