NFATc1 is a central mediator of EGFR-induced ARID1A chromatin dissociation during acinar cell reprogramming


Zhang Z, Wang X, Hamdan FH, Likhobabina A, Patil S, Aperdannier L, Sen M, Traub J, Neesse A, Fischer A, Papantonis A, Singh SK, Ellenrieder V, Johnsen SA, Hessmann E


Cellular and Molecular Gastroenterology and hepatology


Cell Mol Gastroenterol Hepatol. 2023 Feb 7:S2352-345X(23)00018-8.


Background & aims: Loss of AT-rich interactive domain-containing protein 1A (ARID1A) fosters acinar to ductal metaplasia (ADM) and pancreatic carcinogenesis by downregulating transcription programs controlling acinar cell identity. However, how ARID1A reacts to metaplasia-triggering environmental cues remains elusive. Here, we aimed at elucidating the role of ARID1A in controlling ductal pancreatic gene signatures and deciphering hierarchical signaling cues determining ARID1A-dependent chromatin regulation during acinar-cell reprogramming.
Methods: Acinar cell explants with differential ARID1A status were subjected to genome-wide expression analyses. The impact of Epidermal Growth Factor Receptor (EGFR) signaling, NFATc1 activity and ARID1A status on acinar reprogramming processes were characterized by ex vivo ADM assays and transgenic mouse models. EGFR-dependent ARID1A chromatin binding was studied by ChIP-seq analysis and cellular fractionation.
Results: EGFR signaling interferes with ARID1A-dependent transcription by inducing genome-wide ARID1A displacement, thereby phenocopying ARID1A loss-of-function mutations and inducing a shift towards ADM permissive ductal transcription programs. Moreover, we demonstrate that EGFR signaling is required to push ARID1A-deficient acinar cells toward a metaplastic phenotype. Mechanistically, we identified the transcription factor NFATc1 as the central regulatory hub mediating both EGFR signaling-induced genomic ARID1A displacement and the induction of ADM-promoting gene signatures in the absence of ARID1A. Consequently, pharmacological inhibition of NFATc1 or its depletion in transgenic mice not only preserves genome-wide ARID1A occupancy, but also attenuates acinar metaplasia led by ARID1A loss.
Conclusions: Our data describe an intimate relationship between environmental signaling and chromatin remodeling in orchestrating cell fate decisions in the pancreas, and illustrate how ARID1A loss influences transcriptional regulation in acinar cell reprogramming.


Pubmed Link