LIN28

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.{{cite journal | vauthors = Moss EG, Lee RC, Ambros V | title = The cold shock domain protein LIN-28 controls developmental timing in C. elegans and is regulated by the lin-4 RNA | journal = Cell | volume = 88 | issue = 5 | pages = 637–46 | date = Mar 1997 | pmid = 9054503 | doi = 10.1016/s0092-8674(00)81906-6 | s2cid = 13248841 | doi-access = free }} In mice, LIN28 is highly expressed in mouse embryonic stem cells and during early embryogenesis.{{cite journal | vauthors = Yang DH, Moss EG | title = Temporally regulated expression of Lin-28 in diverse tissues of the developing mouse | journal = Gene Expression Patterns | volume = 3 | issue = 6 | pages = 719–26 | date = Dec 2003 | pmid = 14643679 | doi = 10.1016/s1567-133x(03)00140-6 }}

LIN28 is highly expressed in human embryonic stem cells{{cite journal | vauthors = Richards M, Tan SP, Tan JH, Chan WK, Bongso A | title = The transcriptome profile of human embryonic stem cells as defined by SAGE | journal = Stem Cells | volume = 22 | issue = 1 | pages = 51–64 | year = 2004 | pmid = 14688391 | doi = 10.1634/stemcells.22-1-51 | doi-access = free }} and can enhance the efficiency of the formation of induced pluripotent stem (iPS) cells from human fibroblasts.{{cite journal | vauthors = 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 | title = Induced pluripotent stem cell lines derived from human somatic cells | journal = Science | volume = 318 | issue = 5858 | pages = 1917–20 | date = Dec 2007 | pmid = 18029452 | doi = 10.1126/science.1151526 | bibcode = 2007Sci...318.1917Y | s2cid = 86129154 }}

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.{{cite journal | vauthors = 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 | title = Lin28a transgenic mice manifest size and puberty phenotypes identified in human genetic association studies | journal = Nature Genetics | volume = 42 | issue = 7 | pages = 626–30 | date = Jul 2010 | pmid = 20512147 | pmc = 3069638 | doi = 10.1038/ng.593 }} Mutations in LIN28B are associated with precocious puberty.{{cite journal | vauthors = Park SW, Lee ST, Sohn YB, Cho SY, Kim SH, Kim SJ, Kim CH, Ko AR, Paik KH, Kim JW, Jin DK | title = LIN28B polymorphisms are associated with central precocious puberty and early puberty in girls | journal = Korean Journal of Pediatrics | volume = 55 | issue = 10 | pages = 388–92 | date = Oct 2012 | pmid = 23133486 | pmc = 3488615 | doi = 10.3345/kjp.2012.55.10.388 }}

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.{{cite journal | vauthors = 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 | title = The Lin28/let-7 axis regulates glucose metabolism | journal = Cell | volume = 147 | issue = 1 | pages = 81–94 | date = Sep 2011 | pmid = 21962509 | pmc = 3353524 | doi = 10.1016/j.cell.2011.08.033 }} Aberrant expression of LIN28 has been seen to regulate aerobic glycolysis to facilitate cancer proliferation

Mice genetically altered to produce LIN28 during their lifespan showed improved hair growth{{cite journal | vauthors = Shyh-Chang N, Zhu H, Yvanka de Soysa T, Shinoda G, Seligson MT, Tsanov KM, Nguyen L, Asara JM, Cantley LC, Daley GQ | title = Lin28 enhances tissue repair by reprogramming cellular metabolism | journal = Cell | volume = 155 | issue = 4 | date = Nov 2013 | pmid = 24209617 | doi = 10.1016/j.cell.2013.09.059 | pmc=3917449 | pages=778–792}}

• {{cite magazine |vauthors=Fine D |url=http://www.scientificamerican.com/article.cfm?id=new-limb-regeneration-ins |title=New Limb Regeneration Insight Surprises Scientists |date=November 7, 2013 |magazine=Scientific American}} and healthy tissue regeneration on added puncture wounds in later life stages. 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.{{cite journal | vauthors = Shyh-Chang N, Daley GQ | title = Lin28: primal regulator of growth and metabolism in stem cells | journal = Cell Stem Cell | volume = 12 | issue = 4 | date = Apr 2013 | pmid = 23561442 | doi = 10.1016/j.stem.2013.03.005 | pmc=3652335 | pages=395–406}}

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.{{cite journal |last1=Nam |first1=Yunsun |last2=Chen |first2=Casandra |last3=Gregory |first3=Richard I. |last4=Chou |first4=James J. |last5=Sliz |first5=Piotr |title=Molecular Basis for Interaction of let-7 MicroRNAs with Lin28 |journal=Cell |date=November 2011 |volume=147 |issue=5 |pages=1080–1091 |doi=10.1016/j.cell.2011.10.020|pmid=22078496 |pmc=3277843 }}{{cite journal |last1=Loughlin |first1=Fionna E |last2=Gebert |first2=Luca F R |last3=Towbin |first3=Harry |last4=Brunschweiger |first4=Andreas |last5=Hall |first5=Jonathan |last6=Allain |first6=Frédéric H-T |title=Structural basis of pre-let-7 miRNA recognition by the zinc knuckles of pluripotency factor Lin28 |journal=Nature Structural & Molecular Biology |date=11 December 2011 |volume=19 |issue=1 |pages=84–89 |doi=10.1038/nsmb.2202|pmid=22157959 |s2cid=2201304 }} The domains are sufficient for inhibition of let-7 in vivo.{{PDB|3TS2}}; {{cite journal | vauthors = Nam Y, Chen C, Gregory RI, Chou JJ, Sliz P | title = Molecular basis for interaction of let-7 microRNAs with Lin28 | journal = Cell | volume = 147 | issue = 5 | pages = 1080–91 | date = Nov 2011 | pmid = 22078496 | pmc = 3277843 | doi = 10.1016/j.cell.2011.10.020 }}

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

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• {{cite journal | vauthors = Richards M, Tan SP, Tan JH, Chan WK, Bongso A | title = The transcriptome profile of human embryonic stem cells as defined by SAGE | journal = Stem Cells | volume = 22 | issue = 1 | pages = 51–64 | year = 2004 | pmid = 14688391 | doi = 10.1634/stemcells.22-1-51 | doi-access = free }}
• {{cite journal | vauthors = Sempere LF, Freemantle S, Pitha-Rowe I, Moss E, Dmitrovsky E, Ambros V | title = Expression profiling of mammalian microRNAs uncovers a subset of brain-expressed microRNAs with possible roles in murine and human neuronal differentiation | journal = Genome Biology | volume = 5 | issue = 3 | pages = R13 | year = 2004 | pmid = 15003116 | pmc = 395763 | doi = 10.1186/gb-2004-5-3-r13 | doi-access = free }}
• {{cite journal | vauthors = Gerecht-Nir S, Dazard JE, Golan-Mashiach M, Osenberg S, Botvinnik A, Amariglio N, Domany E, Rechavi G, Givol D, Itskovitz-Eldor J | title = Vascular gene expression and phenotypic correlation during differentiation of human embryonic stem cells | journal = Developmental Dynamics | volume = 232 | issue = 2 | pages = 487–97 | date = Feb 2005 | pmid = 15614775 | doi = 10.1002/dvdy.20247 | s2cid = 3006762 | doi-access = free }}
• {{cite journal | vauthors = Lee YS, Kim HK, Chung S, Kim KS, Dutta A | title = Depletion of human micro-RNA miR-125b reveals that it is critical for the proliferation of differentiated cells but not for the down-regulation of putative targets during differentiation | journal = The Journal of Biological Chemistry | volume = 280 | issue = 17 | pages = 16635–41 | date = Apr 2005 | pmid = 15722555 | doi = 10.1074/jbc.M412247200 | doi-access = free}}
• {{cite journal | vauthors = Wu L, Belasco JG | title = Micro-RNA regulation of the mammalian lin-28 gene during neuronal differentiation of embryonal carcinoma cells | journal = Molecular and Cellular Biology | volume = 25 | issue = 21 | pages = 9198–208 | date = Nov 2005 | pmid = 16227573 | pmc = 1265813 | doi = 10.1128/MCB.25.21.9198-9208.2005 }}

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• {{PDBe-KB2|Q9H9Z2|Protein lin-28 homolog A}}

{{PDB Gallery|geneid=79727}}