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 obtained his Bachelor’s degree in Biology from the National & Kapodistrian University of Athens, Greece in 2007 before moving to King’s College London in England to earn his Master’s degree in 2008. In 2013, Dr. Gonatopoulos-Pournatzis obtained his Ph.D. from the University of Dundee in Scotland where he worked in Prof. Victoria Cowling’s laboratory studying mechanisms underlying mRNA cap methylation and gene expression. For his postdoctoral research, he joined Prof. Ben Blencowe’s laboratory at the University of Toronto in Canada to study the regulation and function of splicing regulatory networks in neurons with the support of postdoctoral fellowships from the European Molecular Biology Organization (EMBO), Canadian Institutes of Health Research (CIHR) and Ontario Institute of Regenerative Medicine (OIRM). Dr. Gonatopoulos-Pournatzis has received multiple awards and recognitions, including the Baxter Prize (2012), the Donnelly Centre Research Excellence Award (2018) and his is also a recipient of the 2020 NIH Distinguished Scholar Program. In 2020, Dr. Gonatopoulos-Pournatzis joined the RNA Biology Laboratory at the National Cancer Institute to establish the Functional Transcriptomics Section, which integrates functional genomics and RNA biology. His lab focuses on developing and applying CRISPR tools to systematically uncover transcript variants that play critical roles in normal physiology and disease state.