Project description:Cancers predominantly arise from adult stem cells accumulating somatic driver mutations, but how genetic predisposition affects the penetrance of mutations in tumor initiation is not well understood. Here, we have analyzed gene expression in tumor-prone ApcMin/+ mice on highly variant C57BL/6J and PWD/Ph genetic backgrounds. We show that activation of beta-Catenin-driven and stem cell-specific gene expression in the presence of ApcMin or following APC loss is high in B6 mouse intestines, but remains moderate in intestines carrying PWD/Ph chromosome 5, suggesting that PWD/Ph variants restrict adenoma initiation by controlling stem cell homeostasis. Gene expression of modifier candidates and DNA methylation on chromosome 5 are predominantly cis-controlled and largely reflect the parental patterns, providing a genetic basis for inheritance of tumor susceptibility.
Project description:Cancers predominantly arise from adult stem cells accumulating somatic driver mutations, but how genetic predisposition affects the penetrance of mutations in tumor initiation is not well understood. Here, we have analyzed gene expression in tumor-prone ApcMin/+ mice on highly variant C57BL/6J and PWD/Ph genetic backgrounds. We show that activation of beta-Catenin-driven and stem cell-specific gene expression in the presence of ApcMin or following APC loss is high in B6 mouse intestines, but remains moderate in intestines carrying PWD/Ph chromosome 5, suggesting that PWD/Ph variants restrict adenoma initiation by controlling stem cell homeostasis. Gene expression of modifier candidates and DNA methylation on chromosome 5 are predominantly cis-controlled and largely reflect the parental patterns, providing a genetic basis for inheritance of tumor susceptibility.
Project description:To assess the role of LSD1 in mice small intestinal epithelium, small intestinal organoids were treated with an inhibitor for LSD1 (GSK-LSD1) and compared to untreated organoids. Similar to intestinal epithelium from mice with an intestinal epithelium specific LSD1-KO, paneth cells dissappear upon GSK-LSD1 treatment. We used these sequencing data to show that these small intestinal organoids have a similar phenotype as mice epithelium without LSD1.
Project description:The metabolic pathways that underlie the association between folate deficiency and increased risk for colorectal cancer (CRC) remain unclear. We have studied the effect of C1THF synthase (encoded by the Mthfd1 gene) and dietary folate and choline on intestinal tumor development in Apcmin/+ mice and azoxymethane (AOM)-induced colon cancer in mice. Mthfd1 deficiency did not alter tumor number or load in Apcmin/+ mice, but did result in a decreased incidence of colon tumors. Conversely, Mthfd1 deficiency increased tumor number 3.5-fold and tumor load 2-fold in AOM-treated mice. Here we tested colons isolated from wildtype and Mthfd1-deficient animals for alterations in gene expression. Keywords: genetic modification RNA was isolated from proximal colons of MTHFD heterozygous and wild-type mice raised on a control diet. Three colon samples were isolated from each genotype to provide biological replication.
Project description:Histone acetyltransferases KAT2A and KAT2B are paralogs highly expressed in the intestinal epithelium, but their functions are not well understood. In this study, double knockout of murine Kat2 genes in the intestinal epithelium was lethal, resulting in diminished H3K9ac
expression, loss of stem cells, and robust activation of interferon signaling. Use of pharmacological agents and sterile organoid cultures indicated a cell-intrinsic double-stranded RNA trigger for interferon signaling. Acetyl-proteomics and dsRIP-seq were employed to interrogate the mechanism behind this response, which identified self-derived, mitochondria- encoded double-stranded RNA as the source of intrinsic interferon signaling. KAT2A and KAT2B therefore play an essential role in regulating mitochondrial functions as well as maintaining intestinal health.