Journal Article

DZNE-2023-00451

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png NFATc1 Is a Central Mediator of EGFR-Induced ARID1A Chromatin Dissociation During Acinar Cell Reprogramming.

Zhang, Z. ; Wang, X. ; Hamdan, F. H. ; Likhobabina, A. ; Patil, S. ; Aperdannier, L. ; Sen, M. ; Traub, J. ; Neesse, A. ; Fischer, A.DZNE* ; Papantonis, A. ; Singh, S. K. ; Ellenrieder, V. ; Johnsen, S. A. ; Hessmann, E.

2023
Elsevier New York, NY

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Please use a persistent id in citations: doi:10.1016/j.jcmgh.2023.01.015

Abstract: Loss of AT-rich interactive domain-containing protein 1A (ARID1A) fosters acinar-to-ductal metaplasia (ADM) and pancreatic carcinogenesis by down-regulating transcription programs controlling acinar cell identity. However, how ARID1A reacts to metaplasia-triggering environmental cues remains elusive. Here, we aimed to elucidate the role of ARID1A in controlling ductal pancreatic gene signatures and deciphering hierarchical signaling cues determining ARID1A-dependent chromatin regulation during acinar cell reprogramming.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 chromatin immunoprecipitation sequencing analysis and cellular fractionation.EGFR signaling interferes with ARID1A-dependent transcription by inducing genome-wide ARID1A displacement, thereby phenocopying ARID1A loss-of-function mutations and inducing a shift toward ADM permissive ductal transcription programs. Moreover, we show that EGFR signaling is required to push ARID1A-deficient acinar cells toward a metaplastic phenotype. Mechanistically, we identified the transcription factor nuclear factor of activated T cells 1 (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, pharmacologic 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.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.

Keyword(s): Mice (MeSH) ; Animals (MeSH) ; Acinar Cells: metabolism (MeSH) ; Chromatin (MeSH) ; Pancreatic Neoplasms: genetics (MeSH) ; Carcinoma, Pancreatic Ductal: genetics (MeSH) ; Cellular Reprogramming (MeSH) ; Transcription Factors: genetics (MeSH) ; ErbB Receptors: genetics (MeSH) ; Mice, Transgenic (MeSH) ; Metaplasia (MeSH) ; DNA-Binding Proteins: genetics (MeSH) ; NFATC Transcription Factors: genetics (MeSH) ; NFATC Transcription Factors: metabolism (MeSH) ; Chromatin ; ARID1A ; Acinar-to-Ductal Metaplasia ; EGFR ; NFATc1 ; Pancreas ; Transcription ; Transcription Factors ; ErbB Receptors ; Arid1a protein, mouse ; DNA-Binding Proteins ; Nfatc1 protein, mouse ; NFATC Transcription Factors

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Contributing Institute(s):

1. Epigenetics and Systems Medicine in Neurodegenerative Diseases (AG Fischer 1 ; AG Fischer)

Research Program(s):

1. 352 - Disease Mechanisms (POF4-352) (POF4-352)

Appears in the scientific report 2023

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Database coverage:
; ; ; ; Article Processing Charges ; Clarivate Analytics Master Journal List ; Current Contents - Clinical Medicine ; DOAJ Seal ; Essential Science Indicators ; Fees ; IF >= 5 ; JCR ; PubMed Central ; SCOPUS ; Science Citation Index Expanded ; Web of Science Core Collection

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