Gene isoform

Gene isoforms are mRNAs that are produced from the same locus but are different in their transcription start sites (TSSs), protein coding DNA sequences (CDSs) and/or untranslated regions (UTRs), potentially altering gene function.

Cis-regulatory elements in the promoter contain sequences recognized by transcription factors and the basal transcription machinery. So the location of the TSS is important for understanding the biogenesis of specific isoforms. The idea that different binding partners confer different functional properties has been well studied in tissue-specific gene regulation.[1] For example, the same transcription factor (TF) can direct gene expression in different tissues simply by binding with different TSSs in each tissue.[2] Isoforms harboring changes in the CDS have been the most thoroughly characterized because they commonly give rise to proteins with different functional properties.[3] UTRs regulate the levels of primary transcript in numerous ways: transcript stability, folding and turnover, as well as translation efficiency. UTRs are often the target of miRNA, which typically downregulate transcript expression by triggering degradation or halting translation.[4]

The gene isoforms can be sequenced by Whole Transcriptome Shotgun Sequencing (RNA-Seq).[4] Recently some progress has been made to characterize known isoforms of regeneration associated genes (RAGs) using RNA-Seq, which is important in understanding the isoform diversity in the CNS.[5][6]

Examples

ATF3

Activating transcription factor 3 (Atf3) is a known RAG with numerous promoters. Atf3 expression increases after nerve injury and overexpression of a constitutively active form of Atf3 increases the rate of peripheral nerve regeneration.[7] Four Atf3 isoforms were identified in dorsal root ganglia (DRG) so far. These four isoforms differ in TSS, and one differs in the CDS. However it is unclear which promoters are in use in regenerating DRG neurons.[8]

PTEN

Phosphatase and tensin homolog (Pten) is originally identified as a tumor suppressor gene.[9] Recent studies found that Pten also suppressed axon regeneration in retinal ganglion cells, corticospinal tract, and DRG neurons.[10][11][12] So far 3 Pten isoforms (Pten, PtenJ1, and Pten J2) have been identified and analyzed. Pten J1 is identical in sequence to the conventional Pten isoform except for a difference in TSS and a small shift in the CDS. Pten J2 has a truncated CDS, an alternative transcription start site and a longer 3’ UTR compared to the conventional Pten isoform expressed within neurons. The truncated CDS encodes a protein that lacks a phosphate domain. Also, overexpression of Pten J2 and Pten in primary cortical neurons does not influence axon regeneration. So it’s hypothesized that Pten J2 works as regulatory RNA to inhibit the activity of Pten.[8]

See also

References
  1. Mitchell PJ, Tjian R (July 1989). "Transcriptional regulation in mammalian cells by sequence-specific DNA binding proteins". Science. 245 (4916): 371–8. Bibcode:1989Sci...245..371M. doi:10.1126/science.2667136. PMID 2667136.
  2. Yu X, Lin J, Zack DJ, Qian J (2006). "Computational analysis of tissue-specific combinatorial gene regulation: predicting interaction between transcription factors in human tissues". Nucleic Acids Res. 34 (17): 4925–36. doi:10.1093/nar/gkl595. PMC 1635265. PMID 16982645.
  3. Breitbart RE, Andreadis A, Nadal-Ginard B (1987). "Alternative splicing: a ubiquitous mechanism for the generation of multiple protein isoforms from single genes". Annu. Rev. Biochem. 56: 467–95. doi:10.1146/annurev.bi.56.070187.002343. PMID 3304142.
  4. van der Velden AW, Thomas AA (January 1999). "The role of the 5' untranslated region of an mRNA in translation regulation during development". Int. J. Biochem. Cell Biol. 31 (1): 87–106. doi:10.1016/S1357-2725(98)00134-4. PMID 10216946.
  5. Wu JQ, Habegger L, Noisa P, Szekely A, Qiu C, Hutchison S, Raha D, Egholm M, Lin H, Weissman S, Cui W, Gerstein M, Snyder M (March 2010). "Dynamic transcriptomes during neural differentiation of human embryonic stem cells revealed by short, long, and paired-end sequencing" (PDF). Proc. Natl. Acad. Sci. U.S.A. 107 (11): 5254–9. Bibcode:2010PNAS..107.5254W. doi:10.1073/pnas.0914114107. PMC 2841935. PMID 20194744.
  6. Barbara Treutlein; Ozgun Gokce; Stephen R. Quake; Thomas C. Südhof. "Cartography of neurexin alternative splicing mapped by single-molecule long-read mRNA sequencing". Proceedings of the National Academy of Sciences of the United States of America. 111: E1291–E1299. Bibcode:2014PNAS..111E1291T. doi:10.1073/pnas.1403244111. PMC 3977267. PMID 24639501.
  7. Seijffers R, Mills CD, Woolf CJ (July 2007). "ATF3 increases the intrinsic growth state of DRG neurons to enhance peripheral nerve regeneration". J. Neurosci. 27 (30): 7911–20. doi:10.1523/JNEUROSCI.5313-06.2007. PMID 17652582.
  8. Lerch JK, Kuo F, Motti D, Morris R, Bixby JL, Lemmon VP (2012). "Isoform diversity and regulation in peripheral and central neurons revealed through RNA-Seq". PLoS ONE. 7 (1): e30417. Bibcode:2012PLoSO...7E0417L. doi:10.1371/journal.pone.0030417. PMC 3260295. PMID 22272348.
  9. Lee JO, Yang H, Georgescu MM, Di Cristofano A, Maehama T, Shi Y, Dixon JE, Pandolfi P, Pavletich NP (October 1999). "Crystal structure of the PTEN tumor suppressor: implications for its phosphoinositide phosphatase activity and membrane association". Cell. 99 (3): 323–34. doi:10.1016/S0092-8674(00)81663-3. PMID 10555148.
  10. Park KK, Liu K, Hu Y, Smith PD, Wang C, Cai B, Xu B, Connolly L, Kramvis I, Sahin M, He Z (November 2008). "Promoting axon regeneration in the adult CNS by modulation of the PTEN/mTOR pathway". Science. 322 (5903): 963–6. Bibcode:2008Sci...322..963P. doi:10.1126/science.1161566. PMC 2652400. PMID 18988856.
  11. Christie KJ, Webber CA, Martinez JA, Singh B, Zochodne DW (July 2010). "PTEN inhibition to facilitate intrinsic regenerative outgrowth of adult peripheral axons". J. Neurosci. 30 (27): 9306–15. doi:10.1523/JNEUROSCI.6271-09.2010. PMID 20610765.
  12. Liu K, Lu Y, Lee JK, Samara R, Willenberg R, Sears-Kraxberger I, Tedeschi A, Park KK, Jin D, Cai B, Xu B, Connolly L, Steward O, Zheng B, He Z (September 2010). "PTEN deletion enhances the regenerative ability of adult corticospinal neurons". Nat. Neurosci. 13 (9): 1075–81. doi:10.1038/nn.2603. PMC 2928871. PMID 20694004.
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