LIN28

Last updated
LIN28A
Lin28 - Sliz Laboratory - Harvard Medical School (Cell, 2011).png
Available structures
PDB Ortholog search: PDBe RCSB
Identifiers
Aliases LIN28A , CSDD1, LIN-28, LIN28, ZCCHC1, lin-28A, lin-28 homolog A, Lin28a, LIN28A (gene), Lin-28 homolog A
External IDs OMIM: 611043 MGI: 1890546 HomoloGene: 32592 GeneCards: LIN28A
Orthologs
SpeciesHumanMouse
Entrez

79727

83557

Ensembl

ENSG00000131914

ENSMUSG00000050966

UniProt

Q9H9Z2

Q8K3Y3

RefSeq (mRNA)

NM_024674

NM_145833

RefSeq (protein)

NP_078950

NP_665832

Location (UCSC) Chr 1: 26.41 – 26.43 Mb Chr 4: 133.73 – 133.75 Mb
PubMed search [3] [4]
Wikidata
View/Edit Human View/Edit Mouse

Lin-28 homolog A is a protein that in humans is encoded by the LIN28 gene. [5] [6]

Contents

LIN28 encodes an RNA-binding protein [7] that binds to and enhances the translation of the IGF-2 (insulin-like growth factor 2) mRNA. [8] Lin28 binds to the let-7 pre-microRNA and blocks production of the mature let-7 microRNA in mouse embryonic stem cells. [9] [10] In pluripotent embryonal carcinoma cells, LIN28 is localized in the ribosomes, P-bodies and stress granules. [11]

Function

Stem cell expression

LIN28 is thought to regulate the self-renewal of stem cells. In Caenorhabditis elegans , there is only one Lin28 gene that is expressed and in vertebrates, there are two paralogs present, Lin28a and Lin28b. In nematodes, the LIN28 homolog lin-28 is a heterochronic gene that determines the onset of early larval stages of developmental events in C. elegans, by regulating the self-renewal of nematode stem cells in the skin (called seam cells) and vulva (called VPCs) during development. [12] In mice, LIN28 is highly expressed in mouse embryonic stem cells and during early embryogenesis. [13]

LIN28 is highly expressed in human embryonic stem cells [14] and can enhance the efficiency of the formation of induced pluripotent stem (iPS) cells from human fibroblasts. [15]

Puberty

LIN28 overexpression in mice can cause gigantism and a delay in puberty onset, consistent with human genome-wide association studies suggesting that polymorphisms in the human LIN28B gene are associated with human height and puberty timing. [16] Mutations in LIN28B are associated with precocious puberty. [17]

LIN28 can regulate glucose homeostasis in mammals by increasing insulin-PI3K-mTOR signaling and insulin sensitivity, thereby promoting resistance to high fat diet-induced obesity and type 2 diabetes. [18] Aberrant expression of LIN28 has been seen to regulate aerobic glycolysis to facilitate cancer proliferation

Tissue regeneration

Mice genetically altered to produce LIN28 during their lifespan showed improved hair growth [19] and healthy tissue regeneration on added puncture wounds [19] in later life stages. [19] While the mice could regenerate limbs, they could not repair damaged heart tissue. Appropriate drugs replicated the regeneration in unaltered mice, using the same metabolic paths. The drugs increased the subjects' metabolic rates, evidently causing the body to heal at higher rates. The effects of Lin28a activation faded with age. [19] [20]

Structure

Models of Lin28/let-7 complexes obtained through X-ray crystallography and NMR reveal that two folded domains of Lin28 recognize two distinct RNA regions. [21] [22] The domains are sufficient for inhibition of let-7 in vivo . [10] [23]

Applications

LIN28 is a marker of undifferentiated human embryonic stem cells [14] and has been used to enhance the efficiency of the formation of iPS cells from human fibroblasts. [15]

Related Research Articles

microRNA Small non-coding ribonucleic acid molecule

MicroRNA (miRNA) are small, single-stranded, non-coding RNA molecules containing 21 to 23 nucleotides. Found in plants, animals and some viruses, miRNAs are involved in RNA silencing and post-transcriptional regulation of gene expression. miRNAs base-pair to complementary sequences in mRNA molecules, then gene silence said mRNA molecules by one or more of the following processes:

  1. Cleavage of mRNA strand into two pieces,
  2. Destabilization of mRNA by shortening its poly(A) tail, or
  3. Translation of mRNA into proteins.
<span class="mw-page-title-main">Oct-4</span> Mammalian protein found in Homo sapiens

Oct-4, also known as POU5F1, is a protein that in humans is encoded by the POU5F1 gene. Oct-4 is a homeodomain transcription factor of the POU family. It is critically involved in the self-renewal of undifferentiated embryonic stem cells. As such, it is frequently used as a marker for undifferentiated cells. Oct-4 expression must be closely regulated; too much or too little will cause differentiation of the cells.

<i>Krüppel</i>

Krüppel is a gap gene in Drosophila melanogaster, located on the 2R chromosome, which encodes a zinc finger C2H2 transcription factor. Gap genes work together to establish the anterior-posterior segment patterning of the insect through regulation of the transcription factor encoding pair rule genes. These genes in turn regulate segment polarity genes. Krüppel means "cripple" in German, named for the crippled appearance of mutant larvae, who have failed to develop proper thoracic and anterior segments in the abdominal region. Mutants can also have abdominal mirror duplications.

The Let-7 microRNA precursor was identified from a study of developmental timing in C. elegans, and was later shown to be part of a much larger class of non-coding RNAs termed microRNAs. miR-98 microRNA precursor from human is a let-7 family member. Let-7 miRNAs have now been predicted or experimentally confirmed in a wide range of species (MIPF0000002). miRNAs are initially transcribed in long transcripts called primary miRNAs (pri-miRNAs), which are processed in the nucleus by Drosha and Pasha to hairpin structures of about 70 nucleotide. These precursors (pre-miRNAs) are exported to the cytoplasm by exportin5, where they are subsequently processed by the enzyme Dicer to a ~22 nucleotide mature miRNA. The involvement of Dicer in miRNA processing demonstrates a relationship with the phenomenon of RNA interference.

lin-4 microRNA precursor

In molecular biology lin-4 is a microRNA (miRNA) that was identified from a study of developmental timing in the nematode Caenorhabditis elegans. It was the first to be discovered of the miRNAs, a class of non-coding RNAs involved in gene regulation. miRNAs are transcribed as ~70 nucleotide precursors and subsequently processed by the Dicer enzyme to give a 21 nucleotide product. The extents of the hairpin precursors are not generally known and are estimated based on hairpin prediction. The products are thought to have regulatory roles through complete or partial complementarity to mRNA. The lin-4 gene has been found to lie within a 4.11kb intron of a separate host gene.

mir-133 microRNA precursor family

mir-133 is a type of non-coding RNA called a microRNA that was first experimentally characterised in mice. Homologues have since been discovered in several other species including invertebrates such as the fruitfly Drosophila melanogaster. Each species often encodes multiple microRNAs with identical or similar mature sequence. For example, in the human genome there are three known miR-133 genes: miR-133a-1, miR-133a-2 and miR-133b found on chromosomes 18, 20 and 6 respectively. The mature sequence is excised from the 3' arm of the hairpin. miR-133 is expressed in muscle tissue and appears to repress the expression of non-muscle genes.

mir-199 microRNA precursor

The miR-199 microRNA precursor is a short non-coding RNA gene involved in gene regulation. miR-199 genes have now been predicted or experimentally confirmed in mouse, human and a further 21 other species. microRNAs are transcribed as ~70 nucleotide precursors and subsequently processed by the Dicer enzyme to give a ~22 nucleotide product. The mature products are thought to have regulatory roles through complementarity to mRNA.

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:

mir-1 microRNA precursor family

The miR-1 microRNA precursor is a small micro RNA that regulates its target protein's expression in the cell. microRNAs are transcribed as ~70 nucleotide precursors and subsequently processed by the Dicer enzyme to give products at ~22 nucleotides. In this case the mature sequence comes from the 3' arm of the precursor. The mature products are thought to have regulatory roles through complementarity to mRNA. In humans there are two distinct microRNAs that share an identical mature sequence, and these are called miR-1-1 and miR-1-2.

<span class="mw-page-title-main">Induced pluripotent stem cell</span> Pluripotent stem cell generated directly from a somatic cell

Induced pluripotent stem cells are a type of pluripotent stem cell that can be generated directly from a somatic cell. The iPSC technology was pioneered by Shinya Yamanaka and Kazutoshi Takahashi in Kyoto, Japan, who together showed in 2006 that the introduction of four specific genes, collectively known as Yamanaka factors, encoding transcription factors could convert somatic cells into pluripotent stem cells. Shinya Yamanaka was awarded the 2012 Nobel Prize along with Sir John Gurdon "for the discovery that mature cells can be reprogrammed to become pluripotent."

<span class="mw-page-title-main">TP63</span> Protein-coding gene in the species Homo sapiens

Tumor protein p63, typically referred to as p63, also known as transformation-related protein 63 is a protein that in humans is encoded by the TP63 gene.

<span class="mw-page-title-main">CDX2</span> Protein-coding gene in the species Homo sapiens

Homeobox protein CDX-2 is a protein that in humans is encoded by the CDX2 gene. The CDX2 protein is a homeobox transcription factor expressed in the nuclei of intestinal epithelial cells, playing an essential role in the development and function of the digestive system. CDX2 is part of the ParaHox gene cluster, a group of three highly conserved developmental genes present in most vertebrate species. Together with CDX1 and CDX4, CDX2 is one of three caudal-related genes in the human genome.

<span class="mw-page-title-main">SOX2</span> Transcription factor gene of the SOX family

SRY -box 2, also known as SOX2, is a transcription factor that is essential for maintaining self-renewal, or pluripotency, of undifferentiated embryonic stem cells. Sox2 has a critical role in maintenance of embryonic and neural stem cells.

Vasa is an RNA binding protein with an ATP-dependent RNA helicase that is a member of the DEAD box family of proteins. The vasa gene is essential for germ cell development and was first identified in Drosophila melanogaster, but has since been found to be conserved in a variety of vertebrates and invertebrates including humans. The Vasa protein is found primarily in germ cells in embryos and adults, where it is involved in germ cell determination and function, as well as in multipotent stem cells, where its exact function is unknown.

miR-155 Non-coding RNA in the species Homo sapiens

MiR-155 is a microRNA that in humans is encoded by the MIR155 host gene or MIR155HG. MiR-155 plays a role in various physiological and pathological processes. Exogenous molecular control in vivo of miR-155 expression may inhibit malignant growth, viral infections, and enhance the progression of cardiovascular diseases.

mir-184 Non-coding microRNA molecule

In molecular biology, miR-184 microRNA is a short non-coding RNA molecule. MicroRNAs (miRNAs) function as posttranscriptional regulators of expression levels of other genes by several mechanisms. Several targets for miR-184 have been described, including that of mediators of neurological development, apoptosis and it has been suggested that miR-184 plays an essential role in development.

miR-138

miR-138 is a family of microRNA precursors found in animals, including humans. MicroRNAs are typically transcribed as ~70 nucleotide precursors and subsequently processed by the Dicer enzyme to give a ~22 nucleotide product. The excised region or, mature product, of the miR-138 precursor is the microRNA mir-138.

In molecular biology mir-186 microRNA is a short RNA molecule. MicroRNAs function to regulate the expression levels of other genes by several mechanisms.

In molecular biology mir-241 microRNA is a short RNA molecule. MicroRNAs function to regulate the expression levels of other genes by several mechanisms.

The gene Maelstrom, Mael, creates a protein, which was first located in Drosophila melanogaster in the nuage perinuclear structure and has functionality analogous to the spindle, spn, gene class. Its mammalian homolog is MAEL.

References

  1. 1 2 3 GRCh38: Ensembl release 89: ENSG00000131914 - Ensembl, May 2017
  2. 1 2 3 GRCm38: Ensembl release 89: ENSMUSG00000050966 - Ensembl, May 2017
  3. ↑ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. ↑ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  5. ↑ Moss EG, Tang L (Jun 2003). "Conservation of the heterochronic regulator Lin-28, its developmental expression and microRNA complementary sites". Developmental Biology. 258 (2): 432–42. doi: 10.1016/S0012-1606(03)00126-X . PMID   12798299.
  6. ↑ "Entrez Gene: LIN28 lin-28 homolog (C. elegans)".
  7. ↑ Tsialikas J, Romer-Seibert J (Jul 2015). "LIN28: roles and regulation in development and beyond". Development. 142 (14): 2397–404. doi: 10.1242/dev.117580 . PMID   26199409.
  8. ↑ Polesskaya A, Cuvellier S, Naguibneva I, Duquet A, Moss EG, Harel-Bellan A (May 2007). "Lin-28 binds IGF-2 mRNA and participates in skeletal myogenesis by increasing translation efficiency". Genes & Development. 21 (9): 1125–38. doi:10.1101/gad.415007. PMC   1855237 . PMID   17473174.
  9. ↑ Viswanathan SR, Daley GQ, Gregory RI (Apr 2008). "Selective blockade of microRNA processing by Lin28". Science. 320 (5872): 97–100. Bibcode:2008Sci...320...97V. doi:10.1126/science.1154040. PMC   3368499 . PMID   18292307.
  10. 1 2 Ali PS, Ghoshdastider U, Hoffmann J, Brutschy B, Filipek S (Nov 2012). "Recognition of the let-7g miRNA precursor by human Lin28B". FEBS Letters. 586 (22): 3986–90. doi: 10.1016/j.febslet.2012.09.034 . PMID   23063642. S2CID   28899778.
  11. ↑ Balzer E, Moss EG (2007). "Localization of the developmental timing regulator Lin28 to mRNP complexes, P-bodies and stress granules". RNA Biology. 4 (1): 16–25. doi:10.4161/rna.4.1.4364. PMID   17617744.
  12. ↑ Moss EG, Lee RC, Ambros V (Mar 1997). "The cold shock domain protein LIN-28 controls developmental timing in C. elegans and is regulated by the lin-4 RNA". Cell. 88 (5): 637–46. doi: 10.1016/s0092-8674(00)81906-6 . PMID   9054503. S2CID   13248841.
  13. ↑ Yang DH, Moss EG (Dec 2003). "Temporally regulated expression of Lin-28 in diverse tissues of the developing mouse". Gene Expression Patterns. 3 (6): 719–26. doi:10.1016/s1567-133x(03)00140-6. PMID   14643679.
  14. 1 2 Richards M, Tan SP, Tan JH, Chan WK, Bongso A (2004). "The transcriptome profile of human embryonic stem cells as defined by SAGE". Stem Cells. 22 (1): 51–64. doi: 10.1634/stemcells.22-1-51 . PMID   14688391.
  15. 1 2 Yu J, Vodyanik MA, Smuga-Otto K, Antosiewicz-Bourget J, Frane JL, Tian S, Nie J, Jonsdottir GA, Ruotti V, Stewart R, Slukvin II, Thomson JA (Dec 2007). "Induced pluripotent stem cell lines derived from human somatic cells". Science. 318 (5858): 1917–20. Bibcode:2007Sci...318.1917Y. doi:10.1126/science.1151526. PMID   18029452. S2CID   86129154.
  16. ↑ Zhu H, Shah S, Shyh-Chang N, Shinoda G, Einhorn WS, Viswanathan SR, Takeuchi A, Grasemann C, Rinn JL, Lopez MF, Hirschhorn JN, Palmert MR, Daley GQ (Jul 2010). "Lin28a transgenic mice manifest size and puberty phenotypes identified in human genetic association studies". Nature Genetics. 42 (7): 626–30. doi:10.1038/ng.593. PMC   3069638 . PMID   20512147.
  17. ↑ Park SW, Lee ST, Sohn YB, Cho SY, Kim SH, Kim SJ, Kim CH, Ko AR, Paik KH, Kim JW, Jin DK (Oct 2012). "LIN28B polymorphisms are associated with central precocious puberty and early puberty in girls". Korean Journal of Pediatrics. 55 (10): 388–92. doi:10.3345/kjp.2012.55.10.388. PMC   3488615 . PMID   23133486.
  18. ↑ Zhu H, Shyh-Chang N, Segrè AV, Shinoda G, Shah SP, Einhorn WS, Takeuchi A, Engreitz JM, Hagan JP, Kharas MG, Urbach A, Thornton JE, Triboulet R, Gregory RI, Altshuler D, Daley GQ (Sep 2011). "The Lin28/let-7 axis regulates glucose metabolism". Cell. 147 (1): 81–94. doi:10.1016/j.cell.2011.08.033. PMC   3353524 . PMID   21962509.
  19. 1 2 3 4 Shyh-Chang N, Zhu H, Yvanka de Soysa T, Shinoda G, Seligson MT, Tsanov KM, Nguyen L, Asara JM, Cantley LC, Daley GQ (Nov 2013). "Lin28 enhances tissue repair by reprogramming cellular metabolism". Cell. 155 (4): 778–792. doi:10.1016/j.cell.2013.09.059. PMC   3917449 . PMID   24209617.
  20. ↑ Shyh-Chang N, Daley GQ (Apr 2013). "Lin28: primal regulator of growth and metabolism in stem cells". Cell Stem Cell. 12 (4): 395–406. doi:10.1016/j.stem.2013.03.005. PMC   3652335 . PMID   23561442.
  21. ↑ Nam, Yunsun; Chen, Casandra; Gregory, Richard I.; Chou, James J.; Sliz, Piotr (November 2011). "Molecular Basis for Interaction of let-7 MicroRNAs with Lin28". Cell. 147 (5): 1080–1091. doi:10.1016/j.cell.2011.10.020. PMC   3277843 . PMID   22078496.
  22. ↑ Loughlin, Fionna E; Gebert, Luca F R; Towbin, Harry; Brunschweiger, Andreas; Hall, Jonathan; Allain, Frédéric H-T (11 December 2011). "Structural basis of pre-let-7 miRNA recognition by the zinc knuckles of pluripotency factor Lin28". Nature Structural & Molecular Biology. 19 (1): 84–89. doi:10.1038/nsmb.2202. PMID   22157959. S2CID   2201304.
  23. ↑ PDB: 3TS2 ​; Nam Y, Chen C, Gregory RI, Chou JJ, Sliz P (Nov 2011). "Molecular basis for interaction of let-7 microRNAs with Lin28". Cell. 147 (5): 1080–91. doi:10.1016/j.cell.2011.10.020. PMC   3277843 . PMID   22078496.

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