Mike R. Wilson*, Jake J. Reske*, Jeanne Holladay, Subechhya Neupane, Julie Ngo, Nina Cuthrell, Marc Wegener, Mary Rhodes, Marie Adams, Rachael Sheridan, Galen Hostetter, Fahad T. Alotaibi, Paul J. Yong, Michael S. Anglesio, Bruce A. Lessey, Richard E. Leach, Jose M. Teixeira, Stacey A. Missmer, Asgerally T. Fazleabas, and Ronald L. Chandler. *These authors contributed equally. PMID: 33176148. Journal link. News coverage: MSU Today, WLNS, WILX, Genetic Engineering and Biotechnology News.
Mutations in the SWI/SNF subunit ARID1A are observed in deeply invasive endometriosis and ovarian endometriomas. Here, we show that ARID1A regulates H3K27-acetylation in the normal endometrium, such that loss of ARID1A results in H3K27ac-hyperacetylation at important genomic regions known as super-enhancers. Genetic loss or small molecule inhibition of the histone acetyltransferase P300 in ARID1A-mutant endometrium rescues super-enhancer hyperacetylation and inhibits invasive phenotypes. Specifically, hyperacetylation of the SERPINE1 (PAI-1) super-enhancer drives invasion in ARID1A-mutant endometrium. Our findings suggest that invasive endometriosis may be sensitive to super-enhancer-targeted therapeutics.
SWI/SNF inactivation in the endometrial epithelium leads to loss of epithelial integrity (2020, Human Molecular Genetics)
Jake J. Reske*, Mike R. Wilson*, Jeanne Holladay, Marc Wegener, Marie Adams, and Ronald L. Chandler. *These authors contributed equally. PMID: 33075803. Journal link.
In endometrial cancer, ARID1A is the most frequently mutated subunit within the SWI/SNF chromatin remodeling complex, though mutations in other subunits are also observed. Here, we studied the effects of endometrial mutations in BRG1, which is one of two major catalytic subunits in the complex, and compare them to ARID1A. Through genetic models in human endometrial epithelial cells and mice, we found that BRG1 and ARID1A both normally prevent cellular invasion by promoting expression of epithelial identity genes involved in cellular adhesion and cell-cell junctions, even though they often regulate transcription in opposite ways at other genes across the genome.
Lgr5-positive endothelial progenitor cells occupy a tumor and injury prone niche in the kidney vasa recta (2020, Stem Cell Research)
Mike R. Wilson*, Jeanne Holladay*, Rachael Sheridan, Galen Hostetter, Bree Berghuis, Carrie Graveel, Curt Essenburg, Anderson Peck, Thai H. Ho, Melissa Stanton, and Ronald L. Chandler. *These authors contributed equally. PMID: 32464345. Journal link.
The Leucine Rich Repeat Containing G Protein-Coupled Receptor 5 (LGR5) labels tumor-prone stem cell populations in certain types of tissue. In this study, we show that ARID1A and PIK3CA mutations in LGR5-expressing cells result in renal angiosarcomas in adult mice. We further show that LGR5 labels endothelial progenitor cells within the descending vasa recta of the kidney, which give rise to renal medullary vasculature and are activated in response to ischemic kidney injury.
ATAC-seq normalization method can significantly affect differential accessibility analysis and interpretation (2020, Epigenetics & Chromatin)
The Assay for Transposase-Accessible Chromatin (ATAC-seq) is a recently developed technique used to measure genome-wide chromatin accessibility, or where and to what extent genomic DNA is packaged within cells. This study reveals that analysis comparing ATAC-seq data between multiple cell conditions, such as with or without drug treatment, is not a straightforward procedure and can be heavily influenced by the steps used to analyze the data. Also included is a standardized bioinformatics workflow designed to help researchers appropriately analyze their own ATAC-seq data.
A mouse model of endometriosis mimicking the natural spread of invasive endometrium (2020, Human Reproduction)
Endometriosis is a disease in which cells lining the uterus (endometrium) grow outside of the uterus, causing pain and infertility in 5 to 10% of women. Although mouse models of endometriosis have long been established, most models rely on intraperitoneal injection of uterine fragments, steroid hormone treatments or the use of immune-compromised mice. In this study, through a combination of genetic engineering and surgical approaches, we establish a mouse model of endometriosis which mimics the natural spread of the disease from the uterus to the peritoneum, ovaries and omentum.
ARID1A and PI3-kinase pathway mutations in the endometrium drive epithelial transdifferentiation and collective invasion (2019, Nature Communications)
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. *These authors contributed equally. PMID: 31391455.Journal link. News coverage: MSU Today, The Scientist.
Mutations in the ARID1A and PIK3CA genes are common in diseases originating from the endometrial epithelium, such as endometriosis and endometrial cancer. In this study, genetically engineered mice harboring mutations in both of these genes rapidly develop vaginal bleeding and other signs of endometrial pathology, including cellular invasion. Genomic techniques are then used to study the individual and combined effects of these mutations to understand their respective contributions to endometrial disease.