• What are the causes of microRNA deregulation in various human diseases?
First, microRNAs locate in the disease-causing genomic loci, including minimal regions of loss of heterozygosity (LOH), minimal amplicons, or breakpoint cluster regions (1,2) . For instance, miR-15 and miR-16 locate at chromosome 13q14, a region deleted in more than half of B cell chronic lymphocytic leukemia (CLL)s (B-CLL), and both genes are deleted or down-regulated in the majority (68%) of CLL cases (3) . In contrast, the mi R -17-92 polycistron locates in a genomic region that is amplified in human B-cell lymphomas, and therefore are over-expressed (4) .
Second, microRNA deregulation is caused by abnormal epigenetic patterns, including abnormal DNA methylation and histone-modification patterns (5) . For instance, in normal conditions, the putative promoter region of let -7a -3 gene is heavily methylated in normal human tissues, but hypo-methylated in lung adenocarcinomas. Such promoter demethylation induced reactivation of the let -7a -3 with an oncogenic function and increased proliferation in a lung cancer cell lines (6) . In addition, a berrant hypermethylation leads to miR-9-1 inactivation in human breast cancer (7) .
Third, microRNA deregulation may be caused by abnormalities of the enzymes that are involved in microRNA biogenesis. For example, Otsuka et al. unambiguously showed that miR-24 and miR-93 could target viral large protein (L protein) and phosphoprotein (P protein) genes, and in Dicer1-deficient cells, a lack of host miR-24 and miR-93 was responsible for increased VSV replication (8) .
• How to increase the comprehensiveness of the database?
First, miR2Disease provides submission page that allows other researchers to submit important microRNA-disease relationships that are not documented.
Second, we will use text-mining tools to help us pre-screen Pubmed abstracts that potentially describe the microRNA-disease relationships. To this end, we will collaborate with Dr. Zoran Obradovic's group at Temple University , Philadelphia . Dr. Obradovic's group developed a novel approach on substring selection to expedite literature surveys on manuscript pre-screening (9) .
1. Calin, G.A. and Croce, C.M. (2006) MicroRNA-cancer connection: the beginning of a new tale. Cancer Res , 66 , 7390-7394.
2. Calin, G.A., Sevignani, C., Dumitru, C.D., Hyslop, T., Noch, E., Yendamuri, S., Shimizu, M., Rattan, S., Bullrich, F., Negrini, M. et al. (2004) Human microRNA genes are frequently located at fragile sites and genomic regions involved in cancers. Proc Natl Acad Sci U S A , 101 , 2999-3004.
3. Calin, G.A., Dumitru, C.D., Shimizu, M., Bichi, R., Zupo, S., Noch, E., Aldler, H., Rattan, S., Keating, M., Rai, K. et al. (2002) Frequent deletions and down-regulation of micro- RNA genes miR15 and miR16 at 13q14 in chronic lymphocytic leukemia. Proc Natl Acad Sci U S A , 99 , 15524-15529.
4. He, L., Thomson, J.M., Hemann, M.T., Hernando-Monge, E., Mu, D., Goodson, S., Powers, S., Cordon-Cardo, C., Lowe, S.W., Hannon, G.J. et al. (2005) A microRNA polycistron as a potential human oncogene. Nature , 435 , 828-833.
5. Fraga, M.F. and Esteller, M. (2005) Towards the human cancer epigenome: a first draft of histone modifications. Cell Cycle , 4 , 1377-1381.
6. Brueckner, B., Stresemann, C., Kuner, R., Mund, C., Musch, T., Meister, M., Sultmann, H. and Lyko, F. (2007) The human let-7a-3 locus contains an epigenetically regulated microRNA gene with oncogenic function. Cancer Res , 67 , 1419-1423.
7. Lehmann, U., Hasemeier, B., Christgen, M., Muller, M., Romermann, D., Langer, F. and Kreipe, H. (2008) Epigenetic inactivation of microRNA gene hsa-mir-9-1 in human breast cancer. J Pathol , 214 , 17-24.
8. Otsuka, M., Jing, Q., Georgel, P., New, L., Chen, J., Mols, J., Kang, Y.J., Jiang, Z., Du, X., Cook, R. et al. (2007) Hypersusceptibility to vesicular stomatitis virus infection in Dicer1-deficient mice is due to impaired miR24 and miR93 expression. Immunity , 27 , 123-134.
9. Han, B., Obradovic, Z., Hu, Z.Z., Wu, C.H. and Vucetic, S. (2006) Substring selection for biomedical document classification. Bioinformatics , 22 , 2136-2142.
