ARID1A and PI3-kinase pathway mutations in the endometrium drive epithelial transdifferentiation and collective invasion
| Autor: | Ben A. Johnson, Mary Rhodes, Jake J. Reske, Amanda L. Patterson, Marie Adams, Mike R. Wilson, José A. Teixeira, Jeanne Holladay, Julie Koeman, Hui Shen, Ronald L. Chandler, Ren-Wei Su, Asgerally T. Fazleabas, Niraj Joshi, Richard Leach, Genna E. Wilber |
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| Jazyk: | angličtina |
| Rok vydání: | 2019 |
| Předmět: |
0301 basic medicine
ARID1A General Physics and Astronomy 02 engineering and technology Haploinsufficiency Endometrium Mice Phosphatidylinositol 3-Kinases Endometrial cancer Cell Movement Loss of Function Mutation lcsh:Science Regulation of gene expression Multidisciplinary Transdifferentiation Nuclear Proteins 021001 nanoscience & nanotechnology Chromatin Cell biology DNA-Binding Proteins Gene Expression Regulation Neoplastic medicine.anatomical_structure Cell Transformation Neoplastic Myometrium Female 0210 nano-technology Signal Transduction Epithelial-Mesenchymal Transition Class I Phosphatidylinositol 3-Kinases Science Mice Transgenic Biology General Biochemistry Genetics and Molecular Biology Article Cell Line 03 medical and health sciences Cancer epigenetics medicine Animals Humans Neoplasm Invasiveness Cancer models PI3K/AKT/mTOR pathway Gene Expression Profiling Mesenchymal stem cell General Chemistry Epithelium Endometrial Neoplasms Gene expression profiling Disease Models Animal 030104 developmental biology lcsh:Q Transcription Factors |
| Zdroj: | Nature Communications, Vol 10, Iss 1, Pp 1-18 (2019) Nature Communications |
| ISSN: | 2041-1723 |
| Popis: | 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. PIK3CA mutations and ARID1A loss co-exist in endometrial neoplasms. Here, the authors show that these co-mutations drive gene expression profiles correlated with differential chromatin accessibility and ARID1A binding in the endometrial epithelium, resulting in partial EMT and myometrial invasion. |
| Databáze: | OpenAIRE |
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