Gut microbiota play an important role in regulating the development of the host immune system, metabolic rate, and at times, disease pathogenesis. The factors and mechanisms that mediate interactions between microbiota and the intestinal epithelium are not fully understood. We provide novel evidence that microbiota may control intestinal epithelial stem cell (IESC) proliferation in part through microRNAs (miRNAs). We demonstrate that miRNA profiles differ dramatically across functionally distinct cell types of the mouse jejunal intestinal epithelium and that miRNAs respond to microbiota in a highly cell type-specific manner. Importantly, we also show that miRNAs in IESCs are more prominently regulated by microbiota compared with miRNAs in any other intestinal epithelial cell subtype. We identify miR-375 as one miRNA that is significantly suppressed by the presence of microbiota in IESCs. Using a novel method to knockdown gene and miRNA expression enteroids, we demonstrate that we can knock down gene expression in Lgr5 IESCs. Furthermore, when we knock down miR-375 in IESCs, we observe significantly increased proliferative capacity. Understanding the mechanisms by which microbiota regulate miRNA expression in IESCs and other intestinal epithelial cell subtypes will elucidate a critical molecular network that controls intestinal homeostasis and, given the heightened interest in miRNA-based therapies, may offer novel therapeutic strategies in the treatment of gastrointestinal diseases associated with altered IESC function.

Fibrolamellar carcinoma (FLC) is a unique liver cancer primarily affecting young adults and characterized by a fusion event between DNAJB1 and PRKACA. By analyzing RNA-sequencing data from The Cancer Genome Atlas (TCGA) for >9,100 tumors across ~30 cancer types, we show that the DNAJB1-PRKACA fusion is specific to FLCs. We demonstrate that FLC tumors (n = 6) exhibit distinct messenger RNA (mRNA) and long intergenic non-coding RNA (lincRNA) profiles compared to hepatocellular carcinoma (n = 263) and cholangiocarcinoma (n = 36), the two most common liver cancers. We also identify a set of mRNAs (n = 16) and lincRNAs (n = 4), including LINC00473, that distinguish FLC from ~25 other liver and non-liver cancer types. We confirm this unique FLC signature by analysis of two independent FLC cohorts (n = 20 and 34). Lastly, we validate the overexpression of one specific gene in the FLC signature, carbonic anhydrase XII (CA12), at the protein level by western blot and immunohistochemistry. Both the mRNA and lincRNA signatures support a major role for protein kinase A (PKA) signaling in shaping the FLC gene expression landscape, and present novel candidate FLC oncogenes that merit further investigation.

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Abstract-To identify the genetic factors affecting susceptibility to atherosclerosis, we studied the inheritance of plasma total cholesterol (TC) and HDL cholesterol (HDL-C) concentrations and susceptibility to atherosclerotic lesion formation in an (SM/J[SM]ϫNZB/BlNJ[NZB]) outcross, an (SMϫNZB)F1[F1]ϫSM backcross, and the NXSM recombinant inbred (RI) strain set. After 18 or 26 weeks on the atherogenic diet, lesion sizes in female mice were 160Ϯ110 (SE) m 2 for NZB, 100Ϯ60 for F1, and 3800Ϯ920 for SM. After 0, 4, or 26 weeks on the atherogenic diet, NZB had higher TC and HDL-C levels than either SM or F1. The F1 progeny had TC and HDL-C levels slightly higher than or similar to the SM/J parent, while lesion size in the F1 progeny was more similar to the NZB parent. Among the 15 RI strains, 8 resembled NZB and F1, 3 resembled SM, and 4 were intermediate between NZB and SM for lesion size. For the (SMϫNZB)F1ϫSM backcross offspring, 26 resembled NZB and F1, 7 resembled SM, and 6 were intermediate between NZB and SM for lesion size. There was poor correlation between lesion size and plasma TC or HDL-C in the parental strains and the backcross. These data suggest that resistance to atherosclerosis is determined by at least one major dominant gene contributed by the NZB strain, which we have named Ath8. Ath8 segregates independently of genes controlling TC and HDL-C levels. (Arterioscler Thromb Vasc Biol. 1998;18:615-620.) Key Words: genetics Ⅲ quantitative trait loci analysis Ⅲ atherosclerosis Ⅲ recombinant inbred strains Ⅲ lipids A therosclerosis is an important disease affecting millions of Americans. Many factors, including genetics, behavior, and environment, contribute to the risk of developing atherosclerosis, and great progress has been made in identifying many of these risk factors. The mouse has become a particularly useful tool for identifying genetic factors contributing to many diseases, including atherosclerosis, 1-4 because of the existence of inbred, RI, and mutant strains 5 and the development of molecular techniques allowing for the creation of transgenic 6 and knockout mice. 7 Also, recent developments in mapping technologies have resulted in the development of high-resolution genetic 8 and physical maps of the mouse genome. -10Inbred mouse strains differ in plasma lipoprotein concentrations, responsiveness to high-fat, high-cholesterol diets, and susceptibility to atherosclerotic lesion development, 11,12 thus providing useful tools for identifying genetic factors responsible for these differences.13,14 Two of these inbred strains, SM and NZB, differ in plasma TC and HDL-C concentrations 11,15 and in susceptibility to atherosclerotic lesions.11 When female mice are fed either a chow or a high-fat, high-cholesterol diet, NZB have higher plasma TC and HDL-C concentrations than SM. When consuming a chow diet, neither strain develops atherosclerosis, but when fed the high-fat, high-cholesterol diet, NZB females are resistant to lesion formation, whereas SM females develop large lesions. Because high HD...

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