Ethanol exposure drives colon location specific cell composition changes in a normal colon crypt 3D organoid model.
Matthew Devall, Sarah J Plummer, Jennifer Bryant, Lucas T Jennelle, Stephen Eaton, Christopher H Dampier, Jeroen R Huyghe, Ulrike Peters, Steven M Powell, Graham Casey
Author Information
Matthew Devall: Department of Public Health Sciences, Center for Public Health Genomics, University of Virginia, Charlottesville, VA, USA.
Sarah J Plummer: Department of Public Health Sciences, Center for Public Health Genomics, University of Virginia, Charlottesville, VA, USA.
Jennifer Bryant: Department of Public Health Sciences, Center for Public Health Genomics, University of Virginia, Charlottesville, VA, USA.
Lucas T Jennelle: Department of Public Health Sciences, Center for Public Health Genomics, University of Virginia, Charlottesville, VA, USA.
Stephen Eaton: Department of Public Health Sciences, Center for Public Health Genomics, University of Virginia, Charlottesville, VA, USA.
Christopher H Dampier: Department of Public Health Sciences, Center for Public Health Genomics, University of Virginia, Charlottesville, VA, USA.
Jeroen R Huyghe: Public Health Sciences Division, Fred Hutchinson Cancer Center Research Institute, Seattle, WA, USA.
Ulrike Peters: Public Health Sciences Division, Fred Hutchinson Cancer Center Research Institute, Seattle, WA, USA.
Steven M Powell: Digestive Health Center, University of Virginia, Charlottesville, VA, USA.
Graham Casey: Department of Public Health Sciences, Center for Public Health Genomics, University of Virginia, Charlottesville, VA, USA. gc8r@virginia.edu.
Alcohol is a consistently identified risk factor for colon cancer. However, the molecular mechanism underlying its effect on normal colon crypt cells remains poorly understood. We employed RNA-sequencing to asses transcriptomic response to ethanol exposure (0.2% vol:vol) in 3D organoid lines derived from healthy colon (n = 34). Paired regression analysis identified 2,162 differentially expressed genes in response to ethanol. When stratified by colon location, a far greater number of differentially expressed genes were identified in organoids derived from the left versus right colon, many of which corresponded to cell-type specific markers. To test the hypothesis that the effects of ethanol treatment on colon organoid populations were in part due to differential cell composition, we incorporated external single cell RNA-sequencing data from normal colon biopsies to estimate cellular proportions following single cell deconvolution. We inferred cell-type-specific changes, and observed an increase in transit amplifying cells following ethanol exposure that was greater in organoids from the left than right colon, with a concomitant decrease in more differentiated cells. If this occurs in the colon following alcohol consumption, this would lead to an increased zone of cells in the lower crypt where conditions are optimal for cell division and the potential to develop mutations.
References
Int J Cancer. 2007 Nov 1;121(9):2065-72
[PMID: 17640039]
