Characterization of cell type-specific enhancers in the human pancreas using a massively parallel reporter assay

Authors

• MM Jezek
• M Ioh
• S Baek
• HE Arda

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is an aggressive, often lethal cancer originating from the exocrine compartment of the pancreas. A hallmark of many cancers, including PDAC, is loss of cell identity. Recent evidence suggests that PDAC may originate not only from ductal cells but also from acinar cells, which can transdifferentiate into duct-like states through acinar-to-ductal metaplasia. Therefore, it is crucial to understand the regulatory mechanisms that drive cell type-specific functions. Enhancers are non-coding genetic elements that regulate transcription and are overwhelmingly responsible for cell type-specific gene expression. Additionally, over 80% of disease-associated genetic variants map to enhancer regions. While nearly one million candidate enhancer regions have been identified, the functional characterization of enhancers has been a daunting challenge, particularly at genome-scale. Our lab has identified candidate enhancer elements unique to the five major human pancreas cell types, and digital footprint analysis of chromatin accessibility data revealed that these regions are likely bound by cell type-specific transcription factors, underscoring the cell specificity. To systematically characterize the drivers of cell identity among the unique cell types, and identify disease-relevant sequences, we are using a massively parallel reporter assay to quantify enhancer activity and specificity in healthy pancreas and pancreas cancer cells. The results from this study will advance our understanding of the sequence-based regulatory logic that drives unique cell identities in human pancreas cells and offer insights into how transcriptional programs may become dysfunctional in pancreatic cancer.

Scientific Focus Area: Genetics and Genomics

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