Abstract
Current evidence indicates that the majority of the human genome is transcribed into non-coding RNAs (ncRNAs) (Bertone et al., 2004; Kampa et al., 2004; Cheng et al., 2005; Johnson et al., 2005). The initial studies of the ENCODE pilot project, which has analyzed only 1 % of the human genome, show that 74 to 93% of the bases are transcribed (Birney et al., 2007). The function of short ncRNAs, such as microRNA and piRNA, has been studied by a number of research groups (O'Donnell and Boeke, 2007; Zhang et al., 2007). However, little attention has been given to the functional characterization of the long non-coding transcripts, including those expressed from the introns of protein coding genes. Although there is in the literature one paper describing an intronic RNA (SafJ antisense to the Fas gene involved in the regulation of the alternative splicing in the same locus (Yan et al., 2005), and one paper describing global modification in the gene expression profile following over-expression of intronic segments of the CFTR gene (cystic fibrosis transmembrane conductance regulator) (Hill et al., 2006), the role played by the more than 55,000 non-coding RNAs that are transcribed from the introns of 74% of the genes present in the human genome (Nakaya et al., 2007) remains unexplored. As a result of the thematic research project ‘Identificação de marcadores moleculares para diagnóstico e prognóstico em cancer utilizando microarrays de DNA" (Identification of molecular markers for diagnosis and prognosis in cancer using DNA microarrays) (July 2004 to June de 2008), our group has identified a number of long intronic non-coding transcripts, which levels of expression were correlated to the degree of differentiation of prostate tumors (Reis et al., 2004). Next, we have demonstrated that the expression of a number of intronic transcripts could be modulated by androgen in a prostate cell line (Louro et al., 2007). In the next step, we have studied the expression profile of intronic transcripts in normal liver and kidney tissues and in prostate tumors, using customized microarrays with nearly 30 thousand probes for non-coding intronic RNAs. Surprisingly, we observed that the most abundant intronic ncRNAs are transcribed in genomic loci involved with regulation of transcription, in all three tissues (Nakaya et al., 2007). This phenomenon was not observed for the exonic transcripts, thus suggesting a special role for intronic ncRNAs transcribed from the introns of genes belonging to the regulation of transcription gene category in regulating gene expression. We have also observed that a number of intronic transcripts have a tissue-specific expression profile (Nakaya et al., 2007). The aim of the present thematic research proposal is to investigate the functional implications of intronic ncRNAs in cancer, in gene regulation in normal cells, as well as their possible use as markers of malignancy in a number of cancers. The present project will permit to consolidate in our group the use of cell biology approaches for the study ofncRNAs, a line of work that has been recently introduced in our laboratory. The project is divided into two major parts: A) functional characterization of non-coding RNAs expressed in human tumors; B) identification of novel non-coding RNAs and validation of gene expression profiles as possible tumor markers. (AU)
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