ARID1A and PI3-kinase pathway mutations in the endometrium drive epithelial transdifferentiation and collective invasion

Mike R. Wilson, Jake J. Reske, Jeanne Holladay, Genna E. Wilber, Mary Rhodes, Julie Koeman, Marie Adams, Ben Johnson, Ren-Wei Su, Niraj R. Joshi, Amanda L. Patterson, Hui Shen, Richard E. Leach, Jose M. Teixeira, Asgerally T. Fazleabas and Ronald L. Chandler ()
Additional contact information
Mike R. Wilson: Michigan State University
Jake J. Reske: Michigan State University
Jeanne Holladay: Michigan State University
Genna E. Wilber: Michigan State University
Mary Rhodes: Van Andel Research Institute
Julie Koeman: Van Andel Research Institute
Marie Adams: Van Andel Research Institute
Ben Johnson: Van Andel Research Institute
Ren-Wei Su: Michigan State University
Niraj R. Joshi: Michigan State University
Amanda L. Patterson: Michigan State University
Hui Shen: Van Andel Research Institute
Richard E. Leach: Michigan State University
Jose M. Teixeira: Michigan State University
Asgerally T. Fazleabas: Michigan State University
Ronald L. Chandler: Michigan State University

Nature Communications, 2019, vol. 10, issue 1, 1-18

Abstract: Abstract ARID1A and PI3-Kinase (PI3K) pathway alterations are common in neoplasms originating from the uterine endometrium. Here we show that monoallelic loss of ARID1A in the mouse endometrial epithelium is sufficient for vaginal bleeding when combined with PI3K activation. Sorted mutant epithelial cells display gene expression and promoter chromatin signatures associated with epithelial-to-mesenchymal transition (EMT). We further show that ARID1A is bound to promoters with open chromatin, but ARID1A loss leads to increased promoter chromatin accessibility and the expression of EMT genes. PI3K activation partially rescues the mesenchymal phenotypes driven by ARID1A loss through antagonism of ARID1A target gene expression, resulting in partial EMT and invasion. We propose that ARID1A normally maintains endometrial epithelial cell identity by repressing mesenchymal cell fates, and that coexistent ARID1A and PI3K mutations promote epithelial transdifferentiation and collective invasion. Broadly, our findings support a role for collective epithelial invasion in the spread of abnormal endometrial tissue.

Date: 2019
References: Add references at CitEc
Citations:

Downloads: (external link)
https://www.nature.com/articles/s41467-019-11403-6 Abstract (text/html)

Related works:
This item may be available elsewhere in EconPapers: Search for items with the same title.

Export reference: BibTeX RIS (EndNote, ProCite, RefMan) HTML/Text

Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:10:y:2019:i:1:d:10.1038_s41467-019-11403-6

Ordering information: This journal article can be ordered from
https://www.nature.com/ncomms/

DOI: 10.1038/s41467-019-11403-6

Access Statistics for this article

Nature Communications is currently edited by Nathalie Le Bot, Enda Bergin and Fiona Gillespie

More articles in Nature Communications from Nature
Bibliographic data for series maintained by Sonal Shukla () and Springer Nature Abstracting and Indexing ().