Browsing by Subject "TARGET GENES"

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  • Autio, Reija; Saarela, Matti; Jarvinen, Anna-Kaarina; Hautaniemi, Sampsa; Astola, Jaakko (2009)
  • Kondelin, Johanna; Gylfe, Alexandra E.; Lundgren, Sofie; Tanskanen, Tomas; Hamberg, Jiri; Aavikko, Mervi; Palin, Kimmo; Ristolainen, Heikki; Katainen, Riku; Kaasinen, Eevi; Taipale, Minna; Taipale, Jussi; Renkonen-Sinisalo, Laura; Jarvinen, Heikki; Bohm, Jan; Mecklin, Jukka-Pekka; Vahteristo, Pia; Tuupanen, Sari; Aaltonen, Lauri A.; Pitkanen, Esa (2017)
    Approximately 15% of colorectal cancers exhibit microsatellite instability (MSI), which leads to accumulation of large numbers of small insertions and deletions (indels). Genes that provide growth advantage to cells via loss-of-function mutations in micro-satellites are called MSI target genes. Several criteria to define these genes have been suggested, one of them being simple mutation frequency. Microsatellite mutation rate, however, depends on the length and nucleotide context of the microsatellite. Therefore, assessing the general impact of mismatch repair deficiency on the likelihood of mutation events is paramount when following this approach. To identify MSI target genes, we developed a statistical model for the somatic background indel mutation rate of microsatellites to assess mutation significance. Exome sequencing data of 24 MSI colorectal cancers revealed indels at 54 million mononucleotide microsatellites of three or more nucleotides in length. The top 105 microsatellites from 71 genes were further analyzed in 93 additional MSI colorectal cancers. Mutation significance and estimated clonality of mutations determined the most likely MSI target genes to be the aminoadipate-semialdehyde dehydrogenase AASDH and the solute transporter SLC9A8. Our findings offer a systematic profiling of the somatic background mutation rate in protein-coding mononucleotide microsatellites, allowing a full cataloging of the true targets of MSI in colorectal cancer. (C) 2017 AACR.
  • Junnila, Siina; Kokkola, Arto; Karjalainen-Lindsberg, Marja; Puolakkainen, Pauli; Monni, Outi (2010)
  • Jike, Wuhe; Sablok, Gaurav; Bertorelle, Giorgio; Li, Mingai; Varotto, Claudio (2018)
    MicroRNAs (miRNAs) are small non-coding RNA molecules involved in the post-transcriptional regulation of gene expression in plants. Arundo donax L. is a perennial C-3 grass considered one of the most promising bioenergy crops. Despite its relevance, many fundamental aspects of its biology still remain to be elucidated. In the present study we carried out the first in silico mining and tissue-specific characterization of microRNAs and their putative targets in A. donax. We identified a total of 141 miRNAs belonging to 14 families along with the corresponding primary miRNAs, precursor miRNAs and a total of 462 high-confidence predicted targets and novel target sites were validated by 5'-race. Gene Ontology functional annotation showed that miRNA targets are constituted mainly by transcription factors, but three of the newly validated targets are enzymes involved in novel functions like RNA editing, acyl lipid metabolism and post-Golgi trafficking. Folding variability of pre-miRNA loops and phylogenetic analyses indicate variable selective pressure acting on the different miRNA families. The set of miRNAs identified in this study will pave the road to further miRNA research in Arundo donax and contribute towards a better understanding of miRNA-mediated gene regulatory processes in other bioenergy crops.
  • Laurila, Kirsti; Autio, Reija; Kong, Lingjia; Narva, Elisa; Hussein, Samer; Otonkoski, Timo; Lahesmaa, Riitta; Lahdesmaki, Harri (2014)
  • Shrestha, Kul; Aska, Elli; Tuominen, Minna; Kauppi, Liisa (2021)
    Tumors of Lynch syndrome (LS) patients display high levels of microsatellite instability (MSI), which results from complete loss of DNA mismatch repair (MMR), in line with Knudson’s two-hit hypothesis. Why some organs, in particular those of the gastrointestinal (GI) tract, are prone to tumorigenesis in LS remains unknown. We hypothesized that MMR is haploinsufficient in certain tissues, compromising microsatellite stability in a tissue-specific manner before tumorigenesis. Using mouse genetics, we tested how levels of MLH1, a central MMR protein, affect age- and tissue-specific microsatellite stability in vivo and whether elevated MSI is detectable prior to loss of MMR function and to neoplastic growth. To assess putative tissue-specific MMR haploinsufficiency, we determined relevant molecular phenotypes (MSI, Mlh1 promoter methylation status, MLH1 protein and RNA levels) in jejuna of Mlh1+/− mice and compared them to those in spleen, as well as to MMR-proficient and -deficient controls (Mlh1+/+ and Mlh1−/− mice). While spleen MLH1 levels of Mlh1+/− mice were, as expected, approximately 50 % compared to wildtype mice, MLH1 levels in jejunum varied substantially between individual Mlh1+/− mice and moreover, decreased with age. Mlh1+/− mice with soma-wide Mlh1 promoter methylation often displayed severe MLH1 depletion in jejunum. Reduced (but still detectable) MLH1 levels correlated with elevated MSI in Mlh1+/− jejunum. MSI in jejunum increased with age, while in spleens of the same mice, MLH1 levels and microsatellites remained stable. Thus, MLH1 expression levels are particularly labile in intestine of Mlh1+/− mice, giving rise to tissue-specific MSI long before neoplasia. A similar mechanism likely also operates also in the human GI epithelium and could explain the wide range in age-of-onset of LS-associated tumorigenesis.