Marker-based CRISPR screening reveals a MED12-p63 interaction that activates basal identity in pancreatic ductal adenocarcinoma

Maia-Silva, Diogo, Schier, Allison C, Skopelitis, Damianos, Kechejian, Vahag, Alpsoy, Aktan, Liverpool, Jynelle, Taatjes, Dylan J, Vakoc, Christopher R (October 2023) Marker-based CRISPR screening reveals a MED12-p63 interaction that activates basal identity in pancreatic ductal adenocarcinoma. bioRxiv. (Submitted)

PDF 2023_Marker_based_CRISPR_screening_reveals_a_MED12_preprint.pdf - Submitted Version Available under License Creative Commons Attribution. Download (4MB)

Abstract

The presence of basal lineage characteristics signifies hyper-aggressive human adenocarcinomas of the breast, bladder, and pancreas. However, the biochemical mechanisms that maintain this aberrant cell state are poorly understood. Here we performed marker-based genetic screens in search of factors needed to maintain basal identity in pancreatic ductal adenocarcinoma (PDAC). This approach revealed MED12 as a powerful regulator of the basal cell state in this disease. Using biochemical reconstitution and epigenomics, we show that MED12 carries out this function by bridging the transcription factor p63, a known master regulator of the basal lineage, with the Mediator complex to activate lineage-specific enhancer elements. Consistent with this finding, the growth of basal-like PDAC is hypersensitive to MED12 loss when compared to classical PDAC. Taken together, our comprehensive genetic screens have revealed a biochemical interaction that sustains basal identity in human cancer, which could serve as a target for tumor lineage-directed therapeutics.

Item Type:	Paper
Subjects:	diseases & disorders > cancer diseases & disorders Investigative techniques and equipment Investigative techniques and equipment > CRISPR-Cas9 diseases & disorders > cancer > cancer types > pancreatic cancer diseases & disorders > cancer > cancer types
CSHL Authors:	Skopelitis, Damianos Vakoc, Christopher R. Maia-Silva, Diogo Liverpool, Jynelle Alpsoy, Aktan Kechejian, Vahag
Communities:	CSHL labs > Vakoc lab School of Biological Sciences > Publications
SWORD Depositor:	CSHL Elements
Depositing User:	CSHL Elements
Date:	27 October 2023
Date Deposited:	16 Nov 2023 17:06
Last Modified:	05 Apr 2024 18:23
PMCID:	PMC10634811
Related URLs:	Publisher
URI:	https://repository.cshl.edu/id/eprint/41311

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