Diabetes is associated with markedly accelerated rates of micro- and macrovascular complications that increase morbidity and mortality. Understanding the molecular mechanisms can promote much needed therapeutics.
Recent Advances:
Long noncoding RNAs (lncRNAs) are important regulators of gene regulation and cellular function and are emerging as important players in diabetes and its complications. There are number of examples in which lncRNAs are responsive to hyperglycemia and clearly involved in regulation of genes and pathways associated with the development of diabetic complications.
Critical Issues:
As there are likely thousands of lncRNAs that are expressed in any given tissue, understanding how they are regulated and function in the normal healthy state as well as pathological states is a challenge.
Future Directions:
Further studies in how lncRNAs are involved in the development and progression of diabetic complications as well as development of methods to target dysregulated lncRNAs or evaluate them as biomarkers of early detection of organ dysfunction will be highly beneficial to treating diabetic patients.
Get full access to this article
View all access options for this article.
References
1.
Alvarez-DominguezJR, BaiZ, XuD, YuanB, LoKA, YoonMJ, LimYC, KnollM, SlavovN, ChenS, ChenP, LodishHF, and SunL. De novo reconstruction of adipose tissue transcriptomes reveals long non-coding RNA regulators of brown adipocyte development. Cell Metab, 21: 764–776, 2015.
2.
AlvarezML and DiStefanoJK. Functional characterization of the plasmacytoma variant translocation 1 gene (PVT1) in diabetic nephropathy. PLoS One, 6: e18671, 2011.
3.
AndersonDM, AndersonKM, ChangCL, MakarewichCA, NelsonBR, McAnallyJR, KasaragodP, SheltonJM, LiouJ, Bassel-DubyR, and OlsonEN. A micropeptide encoded by a putative long noncoding RNA regulates muscle performance. Cell, 160: 595–606, 2015.
4.
ArnesL, AkermanI, BalderesDA, FerrerJ, and SusselL. betalinc1 encodes a long noncoding RNA that regulates islet beta-cell formation and function. Genes Dev, 30: 502–507, 2016.
5.
AtanasovskaB, RensenSS, van der SijdeMR, MarsmanG, KumarV, JonkersI, WithoffS, Shiri-SverdlovR, GreveJW, FaberKN, MoshageH, WijmengaC, van de SluisB, HofkerMH, and FuJ. A liver-specific long non-coding RNA with a role in cell viability is elevated in human non-alcoholic steatohepatitis. Hepatology, 66: 794–808, 2017.
6.
AwataT, YamashitaH, KuriharaS, Morita-OhkuboT, MiyashitaY, KatayamaS, MoriK, YoneyaS, KohdaM, OkazakiY, MaruyamaT, ShimadaA, YasudaK, NishidaN, TokunagaK, and KoikeA. A genome-wide association study for diabetic retinopathy in a Japanese population: potential association with a long intergenic non-coding RNA. PLoS One, 9: e111715, 2014.
BennerC, van der MeulenT, CaceresE, TigyiK, DonaldsonCJ, and HuisingMO. The transcriptional landscape of mouse beta cells compared to human beta cells reveals notable species differences in long non-coding RNA and protein-coding gene expression. BMC Genomics, 15: 620, 2014.
9.
BoulberdaaM, ScottE, BallantyneM, GarciaR, DescampsB, AngeliniGD, BrittanM, HunterA, McBrideM, McClureJ, MianoJM, EmanueliC, MillsNL, MountfordJC, and BakerAH. A role for the long noncoding RNA SENCR in commitment and function of endothelial cells. Mol Ther, 24: 978–990, 2016.
10.
BrownCJ, BallabioA, RupertJL, LafreniereRG, GrompeM, TonlorenziR, and WillardHF. A gene from the region of the human X inactivation centre is expressed exclusively from the inactive X chromosome. Nature, 349: 38–44, 1991.
11.
BuckinghamM and RigbyPW. Gene regulatory networks and transcriptional mechanisms that control myogenesis. Dev Cell, 28: 225–238, 2014.
12.
CabiliMN, TrapnellC, GoffL, KoziolM, Tazon-VegaB, RegevA, and RinnJL. Integrative annotation of human large intergenic noncoding RNAs reveals global properties and specific subclasses. Genes Dev, 25: 1915–1927, 2011.
13.
CesanaM, CacchiarelliD, LegniniI, SantiniT, SthandierO, ChinappiM, TramontanoA, and BozzoniI. A long noncoding RNA controls muscle differentiation by functioning as a competing endogenous RNA. Cell, 147: 358–369, 2011.
14.
ChenG, YuD, NianX, LiuJ, KoenigRJ, XuB, and ShengL. LncRNA SRA promotes hepatic steatosis through repressing the expression of adipose triglyceride lipase (ATGL). Sci Rep, 6: 35531, 2016.
15.
ChuC, QuK, ZhongFL, ArtandiSE, and ChangHY. Genomic maps of long noncoding RNA occupancy reveal principles of RNA-chromatin interactions. Mol Cell, 44: 667–678, 2011.
16.
CongrainsA, KamideK, OhishiM, and RakugiH. ANRIL: molecular mechanisms and implications in human health. Int J Mol Sci, 14: 1278–1292, 2013.
da RochaST, TevendaleM, KnowlesE, TakadaS, WatkinsM, and Ferguson-SmithAC. Restricted co-expression of Dlk1 and the reciprocally imprinted non-coding RNA, Gtl2: implications for cis-acting control. Dev Biol, 306: 810–823, 2007.
19.
FadistaJ, VikmanP, LaaksoEO, MolletIG, EsguerraJL, TaneeraJ, StormP, OsmarkP, LadenvallC, PrasadRB, HanssonKB, FinotelloF, UvebrantK, OforiJK, Di CamilloB, KrusU, CilioCM, HanssonO, EliassonL, RosengrenAH, RenstromE, WollheimCB, and GroopL. Global genomic and transcriptomic analysis of human pancreatic islets reveals novel genes influencing glucose metabolism. Proc Natl Acad Sci U S A, 111: 13924–13929, 2014.
20.
ForbesJM and CooperME. Mechanisms of diabetic complications. Physiol Rev, 93: 137–188, 2013.
FrobergJE, YangL, and LeeJT. Guided by RNAs: X-inactivation as a model for lncRNA function. J Mol Biol, 425: 3698–3706, 2013.
23.
GongC and MaquatLE. lncRNAs transactivate STAU1-mediated mRNA decay by duplexing with 3′ UTRs via Alu elements. Nature, 470: 284–288, 2011.
24.
GuttmanM, GarberM, LevinJZ, DonagheyJ, RobinsonJ, AdiconisX, FanL, KoziolMJ, GnirkeA, NusbaumC, RinnJL, LanderES, and RegevA. Ab initio reconstruction of cell type-specific transcriptomes in mouse reveals the conserved multi-exonic structure of lincRNAs. Nat Biotechnol, 28: 503–510, 2010.
25.
HonCC, RamilowskiJA, HarshbargerJ, BertinN, RackhamOJL, GoughJ, DenisenkoE, SchmeierS, PoulsenTM, SeverinJ, LizioM, KawajiH, KasukawaT, ItohM, BurroughsAM, NomaS, DjebaliS, AlamT, MedvedevaYA, TestaAC, LipovichL, YipCW, AbugessaisaI, MendezM, HasegawaA, TangD, LassmannT, HeutinkP, BabinaM, WellsCA, KojimaS, NakamuraY, SuzukiH, DaubCO, de HoonMJL, ArnerE, HayashizakiY, CarninciP, and ForrestARR. An atlas of human long non-coding RNAs with accurate 5′ ends. Nature, 543: 199–204, 2017.
26.
HuarteM, GuttmanM, FeldserD, GarberM, KoziolMJ, Kenzelmann-BrozD, KhalilAM, ZukO, AmitI, RabaniM, AttardiLD, RegevA, LanderES, JacksT, and RinnJL. A large intergenic noncoding RNA induced by p53 mediates global gene repression in the p53 response. Cell, 142: 409–419, 2010.
27.
KapranovP, ChengJ, DikeS, NixDA, DuttaguptaR, WillinghamAT, StadlerPF, HertelJ, HackermullerJ, HofackerIL, BellI, CheungE, DrenkowJ, DumaisE, PatelS, HeltG, GaneshM, GhoshS, PiccolboniA, SementchenkoV, TammanaH, and GingerasTR. RNA maps reveal new RNA classes and a possible function for pervasive transcription. Science, 316: 1484–1488, 2007.
28.
KatoM, CastroNE, and NatarajanR. MicroRNAs: potential mediators and biomarkers of diabetic complications. Free Radic Biol Med, 64: 85–94, 2013.
29.
KatoM, WangM, ChenZ, BhattK, OhHJ, LantingL, DeshpandeS, JiaY, LaiJY, O'ConnorCL, WuY, HodginJB, NelsonRG, BitzerM, and NatarajanR. An endoplasmic reticulum stress-regulated lncRNA hosting a microRNA megacluster induces early features of diabetic nephropathy. Nat Commun, 7: 12864, 2016.
30.
KhalilAM, GuttmanM, HuarteM, GarberM, RajA, Rivea MoralesD, ThomasK, PresserA, BernsteinBE, van OudenaardenA, RegevA, LanderES, and RinnJL. Many human large intergenic noncoding RNAs associate with chromatin-modifying complexes and affect gene expression. Proc Nat Acad Sci U S A, 106: 11667–11672, 2009.
31.
KhanAW, ZiemannM, CorcoranSJ, K NH, OkabeJ, RafehiH, MaxwellSS, EslerMD, and El-OstaA. NET silencing by let-7i in postural tachycardia syndrome. JCI Insight, 2: e90183, 2017.
32.
KornienkoAE, DotterCP, GuenzlPM, GisslingerH, GisslingerB, ClearyC, KralovicsR, PaulerFM, and BarlowDP. Long non-coding RNAs display higher natural expression variation than protein-coding genes in healthy humans. Genome Biol, 17: 14, 2016.
33.
KretzM, SiprashviliZ, ChuC, WebsterDE, ZehnderA, QuK, LeeCS, FlockhartRJ, GroffAF, ChowJ, JohnstonD, KimGE, SpitaleRC, FlynnRA, ZhengGX, AiyerS, RajA, RinnJL, ChangHY, and KhavariPA. Control of somatic tissue differentiation by the long non-coding RNA TINCR. Nature, 493: 231–235, 2013.
LackeyDE and OlefskyJM. Regulation of metabolism by the innate immune system. Nat Rev Endocrinol, 12: 15–28, 2016.
36.
LeungA, TracC, JinW, LantingL, AkbanyA, SaetromP, SchonesDE, and NatarajanR. Novel long noncoding RNAs are regulated by angiotensin II in vascular smooth muscle cells. Circ Res, 113: 266–278, 2013.
37.
LiP, RuanX, YangL, KiesewetterK, ZhaoY, LuoH, ChenY, GucekM, ZhuJ, and CaoH. A liver-enriched long non-coding RNA, lncLSTR, regulates systemic lipid metabolism in mice. Cell Metab, 21: 455–467, 2015.
38.
LiuJY, YaoJ, LiXM, SongYC, WangXQ, LiYJ, YanB, and JiangQ. Pathogenic role of lncRNA-MALAT1 in endothelial cell dysfunction in diabetes mellitus. Cell Death Dis, 5: e1506, 2014.
39.
LiuS, ShengL, MiaoH, SaundersTL, MacDougaldOA, KoenigRJ, and XuB. SRA gene knockout protects against diet-induced obesity and improves glucose tolerance. J Biol Chem, 289: 13000–13009, 2014.
40.
LongJ, BadalSS, YeZ, WangY, AyangaBA, GalvanDL, GreenNH, ChangBH, OverbeekPA, and DaneshFR. Long noncoding RNA Tug1 regulates mitochondrial bioenergetics in diabetic nephropathy. J Clin Invest, 126: 4205–4218, 2016.
41.
MatsumotoA, PasutA, MatsumotoM, YamashitaR, FungJ, MonteleoneE, SaghatelianA, NakayamaKI, ClohessyJG, and PandolfiPP. mTORC1 and muscle regeneration are regulated by the LINC00961-encoded SPAR polypeptide. Nature, 541: 228–232, 2017.
42.
MoranI, AkermanI, van de BuntM, XieR, BenazraM, NammoT, ArnesL, NakicN, Garcia-HurtadoJ, Rodriguez-SeguiS, PasqualiL, Sauty-ColaceC, BeucherA, ScharfmannR, van ArensbergenJ, JohnsonPR, BerryA, LeeC, HarkinsT, GmyrV, PattouF, Kerr-ConteJ, PiemontiL, BerneyT, HanleyN, GloynAL, SusselL, LangmanL, BraymanKL, SanderM, McCarthyMI, RavassardP, and FerrerJ. Human beta cell transcriptome analysis uncovers lncRNAs that are tissue-specific, dynamically regulated, and abnormally expressed in type 2 diabetes. Cell Metab, 16: 435–448, 2012.
43.
QiuGZ, TianW, FuHT, LiCP, and LiuB. Long noncoding RNA-MEG3 is involved in diabetes mellitus-related microvascular dysfunction. Biochem Biophys Res Commun, 471: 135–141, 2016.
44.
QuinnJJ and ChangHY. Unique features of long non-coding RNA biogenesis and function. Nat Rev Genet, 17: 47–62, 2016.
45.
ReddyMA, ChenZ, ParkJT, WangM, LantingL, ZhangQ, BhattK, LeungA, WuX, PuttaS, SaetromP, DevarajS, and NatarajanR. Regulation of inflammatory phenotype in macrophages by a diabetes-induced long noncoding RNA. Diabetes, 63: 4249–4261, 2014.
46.
ReddyMA, ZhangE, and NatarajanR. Epigenetic mechanisms in diabetic complications and metabolic memory. Diabetologia, 58: 443–455, 2015.
47.
SookoianS, RohrC, SalatinoA, DopazoH, GianottiTF, CastanoGO, and PirolaCJ. Genetic variation in long noncoding RNAs and the risk of nonalcoholic fatty liver disease. Oncotarget, 8: 22917–22926, 2017.
48.
SunC, LiuX, YiZ, XiaoX, YangM, HuG, LiuH, LiaoL, and HuangF. Genome-wide analysis of long noncoding RNA expression profiles in patients with non-alcoholic fatty liver disease. IUBMB Life, 67: 847–852, 2015.
49.
SunL, GoffLA, TrapnellC, AlexanderR, LoKA, HacisuleymanE, SauvageauM, Tazon-VegaB, KelleyDR, HendricksonDG, YuanB, KellisM, LodishHF, and RinnJL. Long noncoding RNAs regulate adipogenesis. Proc Natl Acad Sci U S A, 110: 3387–3392, 2013.
50.
ThomasAA, FengB, and ChakrabartiS. ANRIL: a Regulator of VEGF in Diabetic Retinopathy. Invest Ophthalmol Vis Sci, 58: 470–480, 2017.
51.
ThumT and KumarswamyR. The smooth long noncoding RNA SENCR. Arterioscler Thromb Vasc Biol, 34: 1124–1125, 2014.
52.
TsaiMC, ManorO, WanY, MosammaparastN, WangJK, LanF, ShiY, SegalE, and ChangHY. Long noncoding RNA as modular scaffold of histone modification complexes. Science, 329: 689–693, 2010.
WallaceC, SmythDJ, Maisuria-ArmerM, WalkerNM, ToddJA, and ClaytonDG. The imprinted DLK1-MEG3 gene region on chromosome 14q32.2 alters susceptibility to type 1 diabetes. Nat Genet, 42: 68–71, 2010.
55.
WangL, ZhaoY, BaoX, ZhuX, KwokYK, SunK, ChenX, HuangY, JauchR, EstebanMA, SunH, and WangH. LncRNA Dum interacts with Dnmts to regulate Dppa2 expression during myogenic differentiation and muscle regeneration. Cell Res, 25: 335–350, 2015.
56.
YanB, YaoJ, LiuJY, LiXM, WangXQ, LiYJ, TaoZF, SongYC, ChenQ, and JiangQ. lncRNA-MIAT regulates microvascular dysfunction by functioning as a competing endogenous RNA. Circ Res, 116: 1143–1156, 2015.
57.
YiH, PengR, ZhangLY, SunY, PengHM, LiuHD, YuLJ, LiAL, ZhangYJ, JiangWH, and ZhangZ. LincRNA-Gm4419 knockdown ameliorates NF-kappaB/NLRP3 inflammasome-mediated inflammation in diabetic nephropathy. Cell Death Dis, 8: e2583, 2017.
58.
YuX, ZhangY, LiT, MaZ, JiaH, ChenQ, ZhaoY, ZhaiL, ZhongR, LiC, ZouX, MengJ, ChenAK, PuriPL, ChenM, and ZhuD. Long non-coding RNA Linc-RAM enhances myogenic differentiation by interacting with MyoD. Nat Commun, 8: 14016, 2017.
59.
ZhangJ, ChenM, ChenJ, LinS, CaiD, ChenC, and ChenZ. Long noncoding RNA MIAT acts as a biomarker in diabetic retinopathy by absorbing of miR-29b and regulating cell apoptosis. Biosci Rep, 37: pii: BSR20170036, 2017.
60.
ZhaoJ, SunBK, ErwinJA, SongJJ, and LeeJT. Polycomb proteins targeted by a short repeat RNA to the mouse X chromosome. Science, 322: 750–756, 2008.
61.
ZhaoXY, LiS, WangGX, YuQ, and LinJD. A long noncoding RNA transcriptional regulatory circuit drives thermogenic adipocyte differentiation. Mol Cell, 55: 372–382, 2014.
62.
ZhouL, SunK, ZhaoY, ZhangS, WangX, LiY, LuL, ChenX, ChenF, BaoX, ZhuX, WangL, TangLY, EstebanMA, WangCC, JauchR, SunH, and WangH. Linc-YY1 promotes myogenic differentiation and muscle regeneration through an interaction with the transcription factor YY1. Nat Commun, 6: 10026, 2015.
63.
ZhouQ, ChungAC, HuangXR, DongY, YuX, and LanHY. Identification of novel long noncoding RNAs associated with TGF-beta/Smad3-mediated renal inflammation and fibrosis by RNA sequencing. Am J Pathol, 184: 409–417, 2014.
64.
ZhouY, CheunsuchonP, NakayamaY, LawlorMW, ZhongY, RiceKA, ZhangL, ZhangX, GordonFE, LidovHG, BronsonRT, and KlibanskiA. Activation of paternally expressed genes and perinatal death caused by deletion of the Gtl2 gene. Development, 137: 2643–2652, 2010.
