The Department of Biomedicine
BBB seminar

BBB seminar: Hani Goodarzi

Revealing the regulatory code underlying pathological regulation of RNA dynamics in metastasis

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Hani Goodarzi
Department of Biochemistry and Biophysics, University of California, San Francisco, CA, USA

Widespread aberrant splicing is now considered a hallmark of cancer, and many of the resulting transcript isoforms have been functionally implicated in tumorigenesis. However, the underlying regulatory pathways that govern RNA splicing and the extent to which they play a role in cancer progression remain largely unknown. Due to our limited knowledge of splicing regulation, we cannot solely rely on annotated pathways to study changes in transcript isoforms. Moreover, bioinformatic strategies that are often used in discovering transcriptional regulatory pathways often fail to capture the complexities of post-transcriptional regulation. For example, common methodologies for cis-element discovery focus on sequence alone and largely ignore the integral role of the RNA structural code in splicing. To address this challenge, we have developed a computational framework that performs context-aware analysis of alternative splicing events to identify known and novel regulators of RNA processing. Using this approach, we have discovered and partly characterized a previously unknown RNA structural splicing enhancer that drives aberrant splicing in highly metastatic breast cancer. We have identified the associated RNA-binding protein that serves as the trans factor that interacts with this novel SSE. We have shown that this pathway drives metastatic progression in xenograft mouse models and that its activity is strongly associated with poor survival in patients. We have since continued to expand on our computational capabilities to interrogate the splicing code and how its underlying regulatory information is encoded in RNA sequence and structure.

Chairperson: Nils Halberg, Department of Biomedicine