Further studies are needed to better understand this mechanism and how widespread it is among cancer types and treatments.

We introduce the "Promoter-switch" concept as an adaptation mechanism in cancer cells when selective pressure targets TEAD/YAP-bound distal elements, shifting reliance to promoter-centric gene regulation.

We found that amongst the many TFs that gain activity in resistant cells, KLF4 is strictly resistance-specific and its binding is increased at gene promoters. In addition, knocking down KLF4 reduced promoter activity, gene expression of TEAD target genes, and cell growth.

We measured promoter transcripts, finding higher levels in resistance, supporting increased promoter activity. What TFs might confer enhanced promoter activity in resistant cells, and drive gene expression?

Base-pair resolution MCC analysis revealed TF footprints in gene promoters, such as in the FOSL1 gene promoter that included AP-1, SP/KLF and NFYA motifs. These motifs were more protected in resistance from MNase, suggesting increased TF binding and potentially, promoter activity

We mapped the binding sites of FOSL1 - finding that it exhibits strongly promoter-biased genomic binding profile in resistant cells (44% binds near promoters among the ~3,000) compared to acute inhibitor treatment-induced peaks in parental cells.

We suspected that promoters gain activity, and since our colleagues have recently reported @DiscoveryOncology that FOSL1 is crucial for the proliferation of resistant cells…. -

but not in the ANKRD1 locus where we observed loop restoration in resistant cells, and the enhancer remained critical for gene expression.

We tested if enhancers are dispensable for gene regulation in resistance when they do not interact with their cognate promoters. Using CRISPR, we proved that enhancers that are functional in parental cells lose their function in resistance e.g., in the FOSL1 locus…,

Given the restoration of gene expression and YAP binding in resistance, we expected that chromatin loops might follow the same trend but we were wrong. MCC experiments revealed that target promoters exhibited reduced interaction frequency with their enhancers in resistant cells.

The inhibitor suppressed many genes and the chromatin binding of YAP (TEAD cofactor) in parental cells; however, gene expression and YAP binding was restored in resistance. Interestingly, inhibitor treatment and resistance shifted YAP binding to favor promoters.

Exciting news, first preprint from my group @Genentech, led by Vasumathi Kameswaran. We studied TEAD/YAP-addicted mesothelioma cells, and how they resist a pan-TEAD inhibitor. They revert to an old-school way of gene regulation…promoters:

RT @xielablife: Less than one month away from abstract submission deadline for the 2025 GRC/GRS Genome Architecture meeting at the beautifu….

RT @Satpathology: Happy to share our latest study asking whether exhausted T cells can form memory? Terrific work led by Colin Raposo and @….

RT @CartographyBio: On #IDWGS, we celebrate women transforming the way we tackle global challenges. From breaking stereotypes to mentoring….

RT @CalebLareau: PERFF-seq is out today in @NatureGenet! Our recent thread summarizes why we are excited about the prospects of programmabl….

RT @HowardYChang: I am excited to join storied biotech pioneer @Amgen as Chief Scientific Officer and Head of Research. I look forward to p….

wow, an amazing synthetic biology approach, congrats to all involved!.

RT @Mate_Kiss_: Excited to share our work with @HalaszLaszlo, now on bioRxiv, on how the systemic effect of a tumor can remodel the epigeno….

RT @EvanWeberPhD: 🚨We are hiring a Research Assistant to help us supercharge CAR T cells!. Candidates of all experience levels are encourag….