Ultraconserved regions (UCRs) are DNA segments greater than 200 bp in length that are completely conserved among human, rat, and mouse (Bejerano et al., 2004). 481 UCRs have been identified, 225 of which are classified as transcribed ("exonic") or possibly transcribed ("possibly exonic") due to overlap with coding exons. Of the remaining 256 UCRs, termed "non-exonic" UCRs, 100 are located within introns of known genes, and 156 occur in intergenic regions (Bejerano et al., 2004).
Exonic UCRs
Exonic UCRs are believed to play roles in post-transcriptional regulation, such as alternative splicing and mRNA processing (Ni et al., 2007). In humans, 29 exonic UCRs reside in RNA-binding protein genes. (Bejerano et al., 2004). Of those 29, 15 have human and/or mouse EST evidence suggesting the presence of AS-NMD (alternative splicing coupled with nonsense-mediated decay) in those regions. Of the 15, eight are stop codon exons, and the other seven appear to link alternative splicing to NMD regulation via other kinds of splicing events such as exon skipping or activation of a 3' UTR intron (Table 1) (Ni et al., 2007).
In addition, exonic UCRs can be transcribed independently of their host genes. One such example is uc.338, which partially overlaps with the PCBP2 gene (Braconi et al., 2011). Further, exonic UCRs can be transcribed antisense to their host gene transcripts, as is the case with 9 of the 18 exonic transcribed UCRs (T-UCRs) whose expression is differentially regulated between cancer and normal tissues (Calin et al., 2007).
Non-exonic UCRs
Non-exonic UCRs typically occur near genes encoding transcription factors important for animal development, including several homeodomain proteins in the Shh pathway (Sandelin et al., 2004; Woolfe et al., 2005). Non-exonic UCRs might be important for transcriptional cis-regulation, by acting as long-range and/or tissue-specific enhancers (Nobrega, et al., 2003; Calin, et al. 2007; Pennacchio et al., 2006). However, non-exonic UCRs do not function solely as DNA-binding targets. It is reported that ncRNAs such as Evf2 may be transcribed from a subset of non-exonic UCRs, thereby controlling the expression of adjacent transcription factors at both the DNA and RNA levels (Licastro et al., 2010). It is becoming increasingly clear that non-exonic UCRs can serve as both enhancers and transcripts simultaneously.
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References:
Bejerano, G., Pheasant, M., Makunin, I., Stephen, S., Kent, W.J., Mattick, J.S., and Haussler, D. (2004). Ultraconserved elements in the human genome. Science 304, 1321-1325.
Braconi, C., Valeri, N., Kogure, T., Gasparini, P., Huang, N., Nuovo, G.J., Terracciano, L., Croce, C.M., and Patel, T. (2011). Expression and functional role of a transcribed noncoding RNA with an ultraconserved element in hepatocellular carcinoma. Proc Natl Acad Sci U S A 108, 786-791.
Calin, G.A., Liu, C.G., Ferracin, M., Hyslop, T., Spizzo, R., Sevignani, C., Fabbri, M., Cimmino, A., Lee, E.J., Wojcik, S.E., et al. (2007). Ultraconserved regions encoding ncRNAs are altered in human leukemias and carcinomas. Cancer Cell 12, 215-229.
Licastro, D., Gennarino, V.A., Petrera, F., Sanges, R., Banfi, S., and Stupka, E. (2010). Promiscuity of enhancer, coding and non-coding transcription functions in ultraconserved elements. BMC Genomics 11, 151.
Ni, J.Z., Grate, L., Donohue, J.P., Preston, C., Nobida, N., O'Brien, G., Shiue, L., Clark, T.A., Blume, J.E., and Ares, M., Jr. (2007). Ultraconserved elements are associated with homeostatic control of splicing regulators by alternative splicing and nonsense-mediated decay. Genes Dev 21, 708-718.
Nobrega, M.A., Ovcharenko, I., Afzal, V., and Rubin, E.M. (2003). Scanning human gene deserts for long-range enhancers. Science 302, 413.
Pennacchio, L.A., Ahituv, N., Moses, A.M., Prabhakar, S., Nobrega, M.A., Shoukry, M., Minovitsky, S., Dubchak, I., Holt, A., Lewis, K.D., et al. (2006). In vivo enhancer analysis of human conserved non-coding sequences. Nature 444, 499-502.
Sandelin, A., Bailey, P., Bruce, S., Engstrom, P.G., Klos, J.M., Wasserman, W.W., Ericson, J., and Lenhard, B. (2004). Arrays of ultraconserved non-coding regions span the loci of key developmental genes in vertebrate genomes. BMC Genomics 5, 99.
Woolfe, A., Goodson, M., Goode, D.K., Snell, P., McEwen, G.K., Vavouri, T., Smith, S.F., North, P., Callaway, H., Kelly, K., et al. (2005). Highly conserved non-coding sequences are associated with vertebrate development. PLoS Biol 3, e7.