Gene isoform

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In genetics, 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.

Contents

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

Related Research Articles

<span class="mw-page-title-main">Messenger RNA</span> RNA that is read by the ribosome to produce a protein

In molecular biology, messenger ribonucleic acid (mRNA) is a single-stranded molecule of RNA that corresponds to the genetic sequence of a gene, and is read by a ribosome in the process of synthesizing a protein.

<span class="mw-page-title-main">Gene expression</span> Conversion of a genes sequence into a mature gene product or products

Gene expression is the process by which information from a gene is used in the synthesis of a functional gene product that enables it to produce end products, proteins or non-coding RNA, and ultimately affect a phenotype. These products are often proteins, but in non-protein-coding genes such as transfer RNA (tRNA) and small nuclear RNA (snRNA), the product is a functional non-coding RNA. The process of gene expression is used by all known life—eukaryotes, prokaryotes, and utilized by viruses—to generate the macromolecular machinery for life.

<span class="mw-page-title-main">Schwann cell</span> Glial cell type

Schwann cells or neurolemmocytes are the principal glia of the peripheral nervous system (PNS). Glial cells function to support neurons and in the PNS, also include satellite cells, olfactory ensheathing cells, enteric glia and glia that reside at sensory nerve endings, such as the Pacinian corpuscle. The two types of Schwann cells are myelinating and nonmyelinating. Myelinating Schwann cells wrap around axons of motor and sensory neurons to form the myelin sheath. The Schwann cell promoter is present in the downstream region of the human dystrophin gene that gives shortened transcript that are again synthesized in a tissue-specific manner.

<span class="mw-page-title-main">Transcription (biology)</span> Process of copying a segment of DNA into RNA

Transcription is the process of copying a segment of DNA into RNA. The segments of DNA transcribed into RNA molecules that can encode proteins produce messenger RNA (mRNA). Other segments of DNA are transcribed into RNA molecules called non-coding RNAs (ncRNAs).

<span class="mw-page-title-main">Peripherin</span> Protein-coding gene in the species Homo sapiens

Peripherin is a type III intermediate filament protein expressed mainly in neurons of the peripheral nervous system. It is also found in neurons of the central nervous system that have projections toward peripheral structures, such as spinal motor neurons. Its size, structure, and sequence/location of protein motifs is similar to other type III intermediate filament proteins such as desmin, vimentin and glial fibrillary acidic protein. Like these proteins, peripherin can self-assemble to form homopolymeric filamentous networks, but it can also heteropolymerize with neurofilaments in several neuronal types. This protein in humans is encoded by the PRPH gene. Peripherin is thought to play a role in neurite elongation during development and axonal regeneration after injury, but its exact function is unknown. It is also associated with some of the major neuropathologies that characterize amyotropic lateral sclerosis (ALS), but despite extensive research into how neurofilaments and peripherin contribute to ALS, their role in this disease is still unidentified.

<span class="mw-page-title-main">L1 (protein)</span> Mammalian protein found in Homo sapiens

L1, also known as L1CAM, is a transmembrane protein member of the L1 protein family, encoded by the L1CAM gene. This protein, of 200-220 kDa, is a neuronal cell adhesion molecule with a strong implication in cell migration, adhesion, neurite outgrowth, myelination and neuronal differentiation. It also plays a key role in treatment-resistant cancers due to its function. It was first identified in 1984 by M. Schachner who found the protein in post-mitotic mice neurons.

RNA-binding proteins are proteins that bind to the double or single stranded RNA in cells and participate in forming ribonucleoprotein complexes. RBPs contain various structural motifs, such as RNA recognition motif (RRM), dsRNA binding domain, zinc finger and others. They are cytoplasmic and nuclear proteins. However, since most mature RNA is exported from the nucleus relatively quickly, most RBPs in the nucleus exist as complexes of protein and pre-mRNA called heterogeneous ribonucleoprotein particles (hnRNPs). RBPs have crucial roles in various cellular processes such as: cellular function, transport and localization. They especially play a major role in post-transcriptional control of RNAs, such as: splicing, polyadenylation, mRNA stabilization, mRNA localization and translation. Eukaryotic cells express diverse RBPs with unique RNA-binding activity and protein–protein interaction. According to the Eukaryotic RBP Database (EuRBPDB), there are 2961 genes encoding RBPs in humans. During evolution, the diversity of RBPs greatly increased with the increase in the number of introns. Diversity enabled eukaryotic cells to utilize RNA exons in various arrangements, giving rise to a unique RNP (ribonucleoprotein) for each RNA. Although RBPs have a crucial role in post-transcriptional regulation in gene expression, relatively few RBPs have been studied systematically.It has now become clear that RNA–RBP interactions play important roles in many biological processes among organisms.

<span class="mw-page-title-main">CCAAT-enhancer-binding proteins</span> Protein family

CCAAT-enhancer-binding proteins is a family of transcription factors composed of six members, named from C/EBPα to C/EBPζ. They promote the expression of certain genes through interaction with their promoters. Once bound to DNA, C/EBPs can recruit so-called co-activators that in turn can open up chromatin structure or recruit basal transcription factors.

<span class="mw-page-title-main">Neurofibromin 1</span> Mammalian protein found in humans

Neurofibromin 1 (NF1) is a gene in humans that is located on chromosome 17. NF1 codes for neurofibromin, a GTPase-activating protein that negatively regulates RAS/MAPK pathway activity by accelerating the hydrolysis of Ras-bound GTP. NF1 has a high mutation rate and mutations in NF1 can alter cellular growth control, and neural development, resulting in neurofibromatosis type 1. Symptoms of NF1 include disfiguring cutaneous neurofibromas (CNF), café au lait pigment spots, plexiform neurofibromas (PN), skeletal defects, optic nerve gliomas, life-threatening malignant peripheral nerve sheath tumors (MPNST), pheochromocytoma, attention deficits, learning deficits and other cognitive disabilities.

<span class="mw-page-title-main">Nerve injury</span> Damage to nervous tissue

Nerve injury is an injury to a nerve. There is no single classification system that can describe all the many variations of nerve injuries. In 1941, Seddon introduced a classification of nerve injuries based on three main types of nerve fiber injury and whether there is continuity of the nerve. Usually, however, nerve injuries are classified in five stages, based on the extent of damage to both the nerve and the surrounding connective tissue, since supporting glial cells may be involved.

Neuroregeneration involves the regrowth or repair of nervous tissues, cells or cell products. Neuroregenerative mechanisms may include generation of new neurons, glia, axons, myelin, or synapses. Neuroregeneration differs between the peripheral nervous system (PNS) and the central nervous system (CNS) by the functional mechanisms involved, especially in the extent and speed of repair. When an axon is damaged, the distal segment undergoes Wallerian degeneration, losing its myelin sheath. The proximal segment can either die by apoptosis or undergo the chromatolytic reaction, which is an attempt at repair. In the CNS, synaptic stripping occurs as glial foot processes invade the dead synapse.

mir-19 microRNA precursor family

There are 89 known sequences today in the microRNA 19 (miR-19) family but it will change quickly. They are found in a large number of vertebrate species. The miR-19 microRNA precursor is a small non-coding RNA molecule that regulates gene expression. Within the human and mouse genome there are three copies of this microRNA that are processed from multiple predicted precursor hairpins:

<span class="mw-page-title-main">CPEB</span> Protein

CPEB, or cytoplasmic polyadenylation element binding protein, is a highly conserved RNA-binding protein that promotes the elongation of the polyadenine tail of messenger RNA. CPEB is present at postsynaptic sites and dendrites where it stimulates polyadenylation and translation in response to synaptic activity. CPEB most commonly activates the target RNA for translation, but can also act as a repressor, dependent on its phosphorylation state. As a repressor, CPEB interacts with the deadenylation complex and shortens the polyadenine tail of mRNAs. In animals, CPEB is expressed in several alternative splicing isoforms that are specific to particular tissues and functions, including the self-cleaving Mammalian CPEB3 ribozyme. CPEB was first identified in Xenopus oocytes and associated with meiosis; a role has also been identified in the spermatogenesis of Caenorhabditis elegans.

<span class="mw-page-title-main">ATF3</span> Protein-coding gene in the species Homo sapiens

Cyclic AMP-dependent transcription factor ATF-3 is a protein that, in humans, is encoded by the ATF3 gene.

<span class="mw-page-title-main">Peripheral myelin protein 22</span> Protein-coding gene in the species Homo sapiens

Peripheral myelin protein 22 (PMP22), also called Growth arrest-specific protein 3 (GAS-3), is a protein which in humans is encoded by the PMP22 gene. Mutations in PMP22 cause changes in the expression of peripheral myelin protein 22 which can result in several neuropathies.

<span class="mw-page-title-main">STAU1</span> Protein-coding gene in the species Homo sapiens

Double-stranded RNA-binding protein Staufen homolog 1 is a protein that in humans is encoded by the STAU1 gene.

<span class="mw-page-title-main">DNA demethylation</span> Removal of a methyl group from one or more nucleotides within a DNA molecule.

For molecular biology in mammals, DNA demethylation causes replacement of 5-methylcytosine (5mC) in a DNA sequence by cytosine (C). DNA demethylation can occur by an active process at the site of a 5mC in a DNA sequence or, in replicating cells, by preventing addition of methyl groups to DNA so that the replicated DNA will largely have cytosine in the DNA sequence.

<span class="mw-page-title-main">Zinc finger protein 226</span> Protein found in humans

Zinc finger protein 226 is a protein that in humans is encoded by the ZNF226 gene.

<span class="mw-page-title-main">FANTOM</span>

FANTOM is an international research consortium first established in 2000 as part of the RIKEN research institute in Japan. The original meeting gathered international scientists from diverse backgrounds to help annotate the function of mouse cDNA clones generated by the Hayashizaki group. Since the initial FANTOM1 effort, the consortium has released multiple projects that look to understand the mechanisms governing the regulation of mammalian genomes. Their work has generated a large collection of shared data and helped advance biochemical and bioinformatic methodologies in genomics research.

<span class="mw-page-title-main">TET enzymes</span> Family of translocation methylcytosine dioxygenases

The TET enzymes are a family of ten-eleven translocation (TET) methylcytosine dioxygenases. They are instrumental in DNA demethylation. 5-Methylcytosine is a methylated form of the DNA base cytosine (C) that often regulates gene transcription and has several other functions in the genome.

References

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  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. 1 2 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 (2014). "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 (13): 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 . PMC   6672733 . PMID   17652582.
  8. 1 2 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...730417L. 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 . PMC   6632469 . 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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