Abstract
Epigenetic mutations like aberrant DNA methylation, histone modifications, or RNA silencing are found in a number of human diseases. This review article discusses the epigenetic mechanisms involved in neurodegenerative disorders, cardiovascular disorders, auto-immune disorders and genomic imprinting disorders. In addition, emerging epigenetic therapeutic strategies for the treatment of such disorders are presented. Medicinal chemistry campaigns highlighting the efforts of the chemists invested towards the rational design of small molecule inhibitors have also been included. Pleasingly, several classes of epigenetic inhibitors, DNMT, HDAC, BET, HAT, and HMT inhibitors, along with RNA based therapies, have exhibited the potential to emerge as therapeutics in the longer run. It is quite hopeful that epigenetic modulator-based therapies will advance to clinical stage investigations by leaps and bounds.
Keywords: Epigenetics, neurodegenerative disorders, cardiovascular disorders, auto-immune disorder, genomic imprinting disorders, DNA methylation.
[http://dx.doi.org/10.1038/301089a0] [PMID: 6185846]
[http://dx.doi.org/10.1016/S0378-1119(01)00721-1] [PMID: 11707319]
[http://dx.doi.org/10.1101/cshperspect.a019497] [PMID: 26834142]
[http://dx.doi.org/10.1016/j.ejphar.2018.08.021] [PMID: 30125562]
[http://dx.doi.org/10.1038/nrc3130] [PMID: 21941284]
[http://dx.doi.org/10.1056/NEJMra1112635] [PMID: 22894577]
[PMID: 27789692]
[http://dx.doi.org/10.1016/j.pbiomolbio.2015.02.013] [PMID: 25841987]
[http://dx.doi.org/10.3389/fgene.2016.00122] [PMID: 27446204]
[http://dx.doi.org/10.3390/ijms18112387] [PMID: 29125541]
[http://dx.doi.org/10.1523/JNEUROSCI.21-10-03383.2001] [PMID: 11331368]
[http://dx.doi.org/10.1016/j.neuron.2007.02.022] [PMID: 17359920]
[http://dx.doi.org/10.1093/nar/gkx387] [PMID: 28486614]
[http://dx.doi.org/10.1161/CIRCRESAHA.115.305206] [PMID: 26837743]
[http://dx.doi.org/10.1136/jmg.39.2.81] [PMID: 11836355]
[http://dx.doi.org/10.1002/art.23758] [PMID: 18759290]
[http://dx.doi.org/10.1007/BF02686117] [PMID: 17416969]
[http://dx.doi.org/10.1038/nature07925] [PMID: 19424149]
[http://dx.doi.org/10.1073/pnas.1315155110] [PMID: 24284169]
[http://dx.doi.org/10.1101/gad.1563807] [PMID: 17639084]
[http://dx.doi.org/10.1172/JCI35847] [PMID: 18830415]
[http://dx.doi.org/10.1016/j.stem.2007.08.003] [PMID: 18371364]
[http://dx.doi.org/10.1016/j.autrev.2015.05.008] [PMID: 26026695]
[http://dx.doi.org/10.1523/JNEUROSCI.2390-08.2008] [PMID: 19118166]
[http://dx.doi.org/10.1038/jcbfm.2009.253] [PMID: 20010955]
[http://dx.doi.org/10.1016/j.jmb.2014.07.032] [PMID: 25108103]
[http://dx.doi.org/10.1007/s11010-017-3008-y] [PMID: 28316060]
[http://dx.doi.org/10.1161/CIRCRESAHA.117.305781] [PMID: 26038570]
[http://dx.doi.org/10.1016/j.ymthe.2016.10.015] [PMID: 28129115]
[http://dx.doi.org/10.1038/ejhg.2009.83] [PMID: 19471314]
[http://dx.doi.org/10.1002/jbm.a.36562] [PMID: 30478988]
[http://dx.doi.org/10.1038/nrn.2017.46] [PMID: 28515491]
[http://dx.doi.org/10.1146/annurev-pharmtox-010814-124527] [PMID: 25340930]
[http://dx.doi.org/10.1152/physrev.00012.2010] [PMID: 21527733]
[http://dx.doi.org/10.1038/nn.2514] [PMID: 20228804]
[http://dx.doi.org/10.1074/jbc.M402229200] [PMID: 15273246]
[http://dx.doi.org/10.1523/JNEUROSCI.23-06-02112.2003] [PMID: 12657670]
[http://dx.doi.org/10.1073/pnas.1121568109] [PMID: 22371606]
[http://dx.doi.org/10.1038/nrn2763] [PMID: 19888283]
[http://dx.doi.org/10.1098/rstb.2013.0515] [PMID: 25135976]
[http://dx.doi.org/10.1016/j.bcp.2015.11.021] [PMID: 26626188]
[http://dx.doi.org/10.3389/fgene.2018.00579] [PMID: 30555513]
[http://dx.doi.org/10.1111/j.1471-4159.2008.05564.x] [PMID: 18636984]
[http://dx.doi.org/10.1006/excr.2000.5080] [PMID: 11139331]
[http://dx.doi.org/10.1523/JNEUROSCI.3739-12.2013] [PMID: 23616558]
[http://dx.doi.org/10.1016/j.jalz.2008.05.420]
[http://dx.doi.org/10.1007/s13311-013-0206-5] [PMID: 24006238]
[http://dx.doi.org/10.1073/pnas.1221292110] [PMID: 23341638]
[http://dx.doi.org/10.1016/j.ab.2013.01.035] [PMID: 23416183]
[http://dx.doi.org/10.1038/nrneurol.2013.23] [PMID: 23399643]
[http://dx.doi.org/10.1038/nrg2341] [PMID: 18463664]
[http://dx.doi.org/10.1038/384641a0] [PMID: 8967953]
[http://dx.doi.org/10.1073/pnas.0606373103] [PMID: 17142323]
[http://dx.doi.org/10.1073/pnas.0800658105] [PMID: 18669659]
[http://dx.doi.org/10.1523/JNEUROSCI.1639-11.2011] [PMID: 22090490]
[http://dx.doi.org/10.1016/j.clinbiochem.2013.02.009] [PMID: 23454500]
[http://dx.doi.org/10.1038/nchembio848] [PMID: 17173028]
[http://dx.doi.org/10.1074/jbc.M112.431957] [PMID: 23580651]
[http://dx.doi.org/10.1038/ncomms7626] [PMID: 25806427]
[http://dx.doi.org/10.1073/pnas.2637013100] [PMID: 14684836]
[http://dx.doi.org/10.1038/ng.830] [PMID: 21532572]
[http://dx.doi.org/10.1038/46052] [PMID: 10647011]
[http://dx.doi.org/10.1016/j.bbi.2011.01.017] [PMID: 21296655]
[http://dx.doi.org/10.3945/jn.109.104653] [PMID: 19339705]
[http://dx.doi.org/10.1523/JNEUROSCI.0110-07.2007] [PMID: 17537967]
[http://dx.doi.org/10.1073/pnas.0505312102] [PMID: 16249339]
[http://dx.doi.org/10.1186/1741-7015-7-62] [PMID: 19845972]
[http://dx.doi.org/10.1126/science.1166859] [PMID: 19119186]
[http://dx.doi.org/10.1073/pnas.0500398102] [PMID: 16009939]
[http://dx.doi.org/10.3390/ijms21155420] [PMID: 32751461]
[http://dx.doi.org/10.1016/j.neuint.2014.09.012] [PMID: 25290336]
(b)NCT00951834. Sunphenon EGCg (Epigallocatechin-Gallate) in the Early Stage of Alzheimer´s Disease (SUN-AK),. 2009.
[http://dx.doi.org/10.3390/ijms19103199] [PMID: 30332838]
[http://dx.doi.org/10.3389/fphar.2020.00537] [PMID: 32390854]
[http://dx.doi.org/10.1038/npp.2008.229] [PMID: 19145227]
[http://dx.doi.org/10.1046/j.1471-4159.2000.740721.x] [PMID: 10646524]
(b)NCT03533257. Study to assess the safety and biological activity of AMX0035 for the treatment of Alzheimer's Disease (PEGASUS),. , 2018.
(c)NCT02046434. Phenylbutyrate response as a biomarker for Alpha-synuclein clearance from the brain,. 2014.
[http://dx.doi.org/10.21307/ane-2020-004] [PMID: 32214273]
[http://dx.doi.org/10.1084/jem.20081588] [PMID: 18955571]
[http://dx.doi.org/10.2174/1570159X13666151021111609] [PMID: 26487502]
[http://dx.doi.org/10.1186/s13195-020-00746-8] [PMID: 33397436]
[http://dx.doi.org/10.1371/journal.pone.0069964] [PMID: 23922875]
[http://dx.doi.org/10.1097/NEN.0b013e318283114a] [PMID: 23399896]
(b)NCT02149160. Study to Assess the Safety, Tolerability, and Pharmacodynamic (PD) Effects of FRM-0334 in Subjects With Prodromal to Moderate Frontotemporal Dementia With Granulin Mutation, 2014.
[http://dx.doi.org/10.1186/1750-1326-8-7] [PMID: 23356410]
[http://dx.doi.org/10.1021/ja102758v] [PMID: 20614936]
[http://dx.doi.org/10.1016/j.trci.2015.08.001] [PMID: 29854936]
[http://dx.doi.org/10.29245/2572.942X/2017/1.1168]
[http://dx.doi.org/10.1523/JNEUROSCI.3203-08.2008] [PMID: 18987186]
[http://dx.doi.org/10.1371/journal.pone.0116919] [PMID: 25608039]
[http://dx.doi.org/10.1038/nrd2407]
[http://dx.doi.org/10.3390/nu9101122] [PMID: 29036903]
(b)NCT00678431. Randomized Trial of a Nutritional Supplement in Alzheimer's Disease, 2008.
(c)NCT02502253. BDPP Treatment for Mild Cognitive Impairment (MCI) and Prediabetes or Type 2 Diabetes Mellitus (T2DM) (BDPP) , 2015.
[http://dx.doi.org/10.1016/j.bbagrm.2010.08.012] [PMID: 20833281]
[http://dx.doi.org/10.1038/nrn2967] [PMID: 21193853]
[http://dx.doi.org/10.1016/j.pbb.2009.04.005] [PMID: 19376155]
(b)NCT00099710. Curcumin in patients with mild to moderate Alzheimer's Disease,. 2004.
(c)NCT01716637. Short term efficacy and safety of perispinal administration of etanercept in mild to moderate Alzheimer's Disease,. 2012.
(d)NCT01811381. Curcumin and Yoga Therapy for Those at Risk for Alzheimer's Disease, 2013.
(e)NCT02114372. Cognitive Health in Ageing Register: Investigational, Observational and Trial Studies in Dementia Research: Prospective Readiness Cohort Study (CHARIOT:PRO), 2014.
[http://dx.doi.org/10.5607/en.2011.20.1.1] [PMID: 22110357]
[http://dx.doi.org/10.1167/iovs.16-19494] [PMID: 27893888]
[http://dx.doi.org/10.1016/j.ejmech.2015.12.024] [PMID: 26735910]
[http://dx.doi.org/10.1021/acs.jmedchem.8b00151] [PMID: 30028616]
[http://dx.doi.org/10.1021/acsmedchemlett.8b00507] [PMID: 30996781]
[http://dx.doi.org/10.1016/j.bioorg.2020.104109] [PMID: 32768741]
[http://dx.doi.org/10.1021/acsmedchemlett.9b00071] [PMID: 30996816]
[http://dx.doi.org/10.1021/jm400564j] [PMID: 23905680]
[http://dx.doi.org/10.1016/j.ejmech.2020.112193] [PMID: 32151835]
[http://dx.doi.org/10.1016/j.nlm.2012.02.008] [PMID: 22426465]
[http://dx.doi.org/10.1021/acschemneuro.8b00648] [PMID: 30525452]
[http://dx.doi.org/10.1021/acschemneuro.9b00303] [PMID: 31441641]
[http://dx.doi.org/10.1021/jm4011884] [PMID: 24261862]
[http://dx.doi.org/10.1021/acschemneuro.8b00600] [PMID: 30511829]
[http://dx.doi.org/10.1021/acschemneuro.8b00116] [PMID: 29932631]
[http://dx.doi.org/10.1021/acsmedchemlett.7b00012] [PMID: 28523102]
[http://dx.doi.org/10.1021/acsmedchemlett.8b00099] [PMID: 30258535]
[http://dx.doi.org/10.1021/cn500021p] [PMID: 24780082]
[http://dx.doi.org/10.1021/acsomega.9b01950] [PMID: 31656902]
[http://dx.doi.org/10.1373/49.8.1292] [PMID: 12881445]
[http://dx.doi.org/10.1111/j.1365-2796.2007.01777.x] [PMID: 17444888]
[http://dx.doi.org/10.1093/eurheartj/ehs091] [PMID: 22511653]
[http://dx.doi.org/10.1016/j.ajhg.2011.03.003] [PMID: 21457905]
[http://dx.doi.org/10.1093/hmg/ddt326] [PMID: 23842454]
[http://dx.doi.org/10.1097/MOL.0b013e32834f319d] [PMID: 22186662]
[http://dx.doi.org/10.4161/epi.6.4.14961] [PMID: 21364323]
[PMID: 20190686]
[http://dx.doi.org/10.1046/j.1529-8817.2004.00081.x] [PMID: 15180700]
[http://dx.doi.org/10.1007/s12195-014-0325-z] [PMID: 24883126]
[http://dx.doi.org/10.1161/CIRCRESAHA.115.303883] [PMID: 24755985]
[http://dx.doi.org/10.1016/j.biomaterials.2017.11.033] [PMID: 29182961]
[http://dx.doi.org/10.1038/ng.1068] [PMID: 22267199]
[http://dx.doi.org/10.1101/gad.2018511] [PMID: 21289070]
[http://dx.doi.org/10.1016/j.athoracsur.2017.04.046] [PMID: 28760462]
[http://dx.doi.org/10.2119/molmed.2017.00012] [PMID: 28805231]
[http://dx.doi.org/10.1016/j.carpath.2015.11.001] [PMID: 26764138]
[http://dx.doi.org/10.1093/eurheartj/ehv290] [PMID: 26112889]
[http://dx.doi.org/10.1007/s11357-015-9804-y] [PMID: 26099749]
[http://dx.doi.org/10.1016/B978-0-12-378638-8.00011-7]
[http://dx.doi.org/10.1016/j.arr.2017.08.001] [PMID: 28789901]
[http://dx.doi.org/10.1016/j.yjmcc.2014.12.023] [PMID: 25579854]
[http://dx.doi.org/10.1016/j.tem.2016.04.015] [PMID: 27210897]
[http://dx.doi.org/10.1038/nrneph.2017.5] [PMID: 28163307]
[http://dx.doi.org/10.1016/j.molmed.2017.02.005] [PMID: 28285806]
[http://dx.doi.org/10.1016/j.yjmcc.2008.08.015] [PMID: 18926829]
[http://dx.doi.org/10.1089/dna.2012.1787] [PMID: 23121236]
[http://dx.doi.org/10.1016/j.cell.2007.03.030] [PMID: 17397913]
[http://dx.doi.org/10.1016/j.trsl.2012.12.004] [PMID: 23274306]
[http://dx.doi.org/10.1074/jbc.M211762200] [PMID: 12477714]
[http://dx.doi.org/10.1074/jbc.M303113200] [PMID: 12761226]
[http://dx.doi.org/10.1161/CIRCULATIONAHA.105.559724] [PMID: 16380549]
[http://dx.doi.org/10.1172/JCI19137] [PMID: 12975471]
[http://dx.doi.org/10.1074/jbc.M305911200] [PMID: 12851393]
[http://dx.doi.org/10.1152/ajpheart.00866.2008] [PMID: 19448146]
[http://dx.doi.org/10.1074/jbc.M403618200] [PMID: 15131116]
[http://dx.doi.org/10.1161/CIRCULATIONAHA.104.519025] [PMID: 16116050]
[http://dx.doi.org/10.1371/journal.pone.0008564] [PMID: 20084101]
[http://dx.doi.org/10.1161/CIRCULATIONAHA.111.040071] [PMID: 22025602]
[http://dx.doi.org/10.1111/j.1365-2443.2008.01252.x] [PMID: 19077033]
[http://dx.doi.org/10.1530/JME-19-0170] [PMID: 31600719]
[http://dx.doi.org/10.1016/j.atherosclerosis.2016.01.036] [PMID: 26868508]
[http://dx.doi.org/10.1164/rccm.201905-0993LE] [PMID: 31419391]
[http://dx.doi.org/10.1038/nrd.2017.125] [PMID: 28660902]
[http://dx.doi.org/10.1186/s12933-015-0260-x] [PMID: 26249018]
[http://dx.doi.org/10.1161/CIRCRESAHA.113.301071] [PMID: 23421989]
[http://dx.doi.org/10.1152/japplphysiol.00006.2018] [PMID: 30284520]
[http://dx.doi.org/10.1016/j.tcm.2012.12.006] [PMID: 23499301]
[http://dx.doi.org/10.1161/CIRCULATIONAHA.113.002416] [PMID: 24396039]
[http://dx.doi.org/10.1016/j.yjmcc.2019.04.003] [PMID: 30978343]
[http://dx.doi.org/10.1021/jm200388e] [PMID: 21650221]
[http://dx.doi.org/10.1172/JCI33160] [PMID: 18292809]
[http://dx.doi.org/10.1016/j.cbi.2015.09.025] [PMID: 26428355]
[http://dx.doi.org/10.1152/ajpcell.00058.2015] [PMID: 26224577]
[http://dx.doi.org/10.1177/1074248415591698] [PMID: 26130616]
[http://dx.doi.org/10.1111/jcmm.12248] [PMID: 24571348]
[http://dx.doi.org/10.12659/MSM.897266] [PMID: 27411964]
[http://dx.doi.org/10.1371/journal.pone.0160920] [PMID: 27504893]
[http://dx.doi.org/10.1126/scitranslmed.aaf1475]
[http://dx.doi.org/10.1161/CIRCRESAHA.118.311227] [PMID: 29748367]
[http://dx.doi.org/10.1146/annurev.genom.2.1.153] [PMID: 11701647]
[http://dx.doi.org/10.1093/hmg/ddg067] [PMID: 12668598]
[http://dx.doi.org/10.1136/jmg.38.12.810] [PMID: 11748303]
[http://dx.doi.org/10.1146/annurev.cellbio.19.111401.092717] [PMID: 14570570]
[http://dx.doi.org/10.1210/en.2003-0681] [PMID: 12960026]
[http://dx.doi.org/10.1093/hmg/dds465] [PMID: 23118352]
[http://dx.doi.org/10.1111/cge.12143] [PMID: 23495910]
[http://dx.doi.org/10.1016/j.cell.2007.05.042] [PMID: 17632057]
[http://dx.doi.org/10.1038/nature06008] [PMID: 17603471]
[http://dx.doi.org/10.1038/ncb1403] [PMID: 16570078]
[http://dx.doi.org/10.1111/j.1469-8749.1965.tb07844.x]
[http://dx.doi.org/10.1038/351665a0] [PMID: 1675767]
[http://dx.doi.org/10.1086/320120] [PMID: 11283796]
[http://dx.doi.org/10.1111/j.1399-0004.2011.01822.x] [PMID: 22150955]
[http://dx.doi.org/10.1136/jmg.29.4.221] [PMID: 1583639]
[http://dx.doi.org/10.1136/jmg.34.1.6] [PMID: 9032641]
[http://dx.doi.org/10.1007/s004390050526] [PMID: 9272165]
[http://dx.doi.org/10.1007/s004310050064] [PMID: 10789928]
[http://dx.doi.org/10.1038/sj.ejhg.5200164] [PMID: 9781054]
[http://dx.doi.org/10.1007/s00439-002-0787-2] [PMID: 12215843]
[http://dx.doi.org/10.1136/jmg.2004.028936] [PMID: 15863658]
[http://dx.doi.org/10.1172/JCI106149] [PMID: 4309802]
[http://dx.doi.org/10.1073/pnas.85.7.2081] [PMID: 3127824]
[PMID: 11588148]
[http://dx.doi.org/10.1136/jmg.30.2.101] [PMID: 8383205]
[http://dx.doi.org/10.1210/jcem.87.1.8133] [PMID: 11788646]
[http://dx.doi.org/10.1073/pnas.95.26.15475] [PMID: 9860993]
[http://dx.doi.org/10.1073/pnas.96.7.3830] [PMID: 10097123]
[http://dx.doi.org/10.1002/(SICI)1521-1878(200005)22:5<452:AID-BIES7>3.0.CO;2-K] [PMID: 10797485]
[http://dx.doi.org/10.1038/nature05913] [PMID: 17522671]
[PMID: 27377127]
[http://dx.doi.org/10.1186/s13148-017-0358-y] [PMID: 28572863]
[http://dx.doi.org/10.1056/NEJMoa0707865] [PMID: 18204098]
[http://dx.doi.org/10.1080/03009740902758875] [PMID: 19444718]
[http://dx.doi.org/10.1002/art.1780331109] [PMID: 2242063]
[http://dx.doi.org/10.1038/nrm4043] [PMID: 26296162]
[http://dx.doi.org/10.1016/j.sbi.2015.09.007] [PMID: 26496625]
[http://dx.doi.org/10.1038/nature14192] [PMID: 25592537]
[http://dx.doi.org/10.1016/j.tig.2004.06.009] [PMID: 15262407]
[http://dx.doi.org/10.1080/15476286.2016.1236170] [PMID: 27819523]
[http://dx.doi.org/10.1038/77023] [PMID: 10888872]
[http://dx.doi.org/10.7759/cureus.620] [PMID: 27382528]
[http://dx.doi.org/10.1073/pnas.1603712113] [PMID: 27162351]
[http://dx.doi.org/10.1038/ncomms13555] [PMID: 27898055]
[http://dx.doi.org/10.1097/MIB.0000000000000990] [PMID: 27930411]
[http://dx.doi.org/10.1016/j.tig.2015.10.007] [PMID: 26704082]
[http://dx.doi.org/10.1038/nrm3941] [PMID: 25650798]
[http://dx.doi.org/10.1073/pnas.0904715106] [PMID: 19571010]
[http://dx.doi.org/10.1136/ard.2010.143040] [PMID: 21515604]
[http://dx.doi.org/10.1002/art.37738] [PMID: 23045159]
[http://dx.doi.org/10.1016/j.jaut.2013.02.002] [PMID: 23478041]
[http://dx.doi.org/10.1016/j.jaut.2015.07.009] [PMID: 26235382]
[http://dx.doi.org/10.1210/er.2013-1055] [PMID: 24091783]
[http://dx.doi.org/10.3389/fimmu.2017.00396] [PMID: 28439272]
[http://dx.doi.org/10.1186/s13148-019-0632-2] [PMID: 30808407]
[PMID: 8675578]
[http://dx.doi.org/10.1021/acs.jmedchem.7b01593] [PMID: 29589441]
[http://dx.doi.org/10.1021/acsmedchemlett.0c00302] [PMID: 32676157]