Decoding the role of alternative isoforms in cancer

Kaia Mattioli, PhD
Postdoctoral researcher
Department of Medicine, Division of Genetics
Brigham & Women’s Hospital
Harvard Medical School
Boston, MA, USA
 

This conference is hosted by François Robert, PhD, Director of the Chromatin and Genomic Expression Research Unit.

About this conference
Genes are often described as the functional units of the genome, but this is a convenient abstraction. In reality, genes are modular collections of exons that are assembled in myriad ways to produce distinct mRNAs, which are translated into distinct protein isoforms. In cancer, RNA processing often goes awry, leading to widespread misexpression of isoforms. Despite a few well-characterized examples, we lack a systematic understanding of how isoforms diversify the functions of their host genes. In this talk, I will present evidence that this gene-level view obscures cancer-relevant biology. First, I will describe our efforts to characterize alternative isoforms of an important class of regulatory proteins—transcription factors—using functional assays. We discovered that two-thirds of alternative transcription factor isoforms functionally differ from reference isoforms, and often act as negative regulators, which are preferentially misregulated in tumors. This work motivates my future research program, which will leverage and develop functional genomics approaches—including long-read RNA sequencing and RNA-targeting CRISPR systems—to understand how individual isoforms causally contribute to breast cancer phenotypes such as proliferation and drug resistance.

About Kaia Mattioli
Dr. Kaia Mattioli is a K99/R00 fellow in Dr. Martha Bulyk’s lab at Brigham and Women’s Hospital and Harvard Medical School. Kaia is fascinated by the complexity of the human genome. She is interested in understanding how aberrant RNA processing contributes to cancer. Her research combines computational and experimental isoform-resolved functional genomics to probe how alternative isoforms modulate gene regulatory networks in breast cancer cells. Kaia completed her PhD in Dr. John Rinn’s lab at Harvard University and her BS in biological sciences at Stanford University.

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