CpG and Non-CpG Methylation in Epigenetic Gene Regulation and Brain Function

Genes - Tập 8 Số 6 - Trang 148
Hyun Gyung Jang1, Woo Yong Shin1, Jeong‐Bong Lee1, Jeong Tae1
1Department of Stem Cell and Regenerative Biotechnology, KU Institute of Science and Technology, Konkuk University, Seoul 143-701, Korea.

Tóm tắt

DNA methylation is a major epigenetic mark with important roles in genetic regulation. Methylated cytosines are found primarily at CpG dinucleotides, but are also found at non-CpG sites (CpA, CpT, and CpC). The general functions of CpG and non-CpG methylation include gene silencing or activation depending on the methylated regions. CpG and non-CpG methylation are found throughout the whole genome, including repetitive sequences, enhancers, promoters, and gene bodies. Interestingly, however, non-CpG methylation is restricted to specific cell types, such as pluripotent stem cells, oocytes, neurons, and glial cells. Thus, accumulation of methylation at non-CpG sites and CpG sites in neurons seems to be involved in development and disease etiology. Here, we provide an overview of CpG and non-CpG methylation and their roles in neurological diseases.

Từ khóa


Tài liệu tham khảo

Russo, V.E., Martienssen, R.A., and Riggs, A.D. (1996). Epigenetic Mechanisms of Gene Regulation, Cold Spring Harbor Laboratory Press.

Portela, 2010, Epigenetic modifications and human disease, Nat. Biotechnol., 28, 1057, 10.1038/nbt.1685

Riggs, 1975, X inactivation, differentiation, and DNA methylation, Cytogenet. Genome Res., 14, 9, 10.1159/000130315

Holliday, 1975, DNA modification mechanisms and gene activity during development, Science, 187, 226, 10.1126/science.187.4173.226

Christman, 2002, 5-azacytidine and 5-aza-2′-deoxycytidine as inhibitors of DNA methylation: Mechanistic studies and their implications for cancer therapy, Oncogene, 21, 5483, 10.1038/sj.onc.1205699

Lindroth, 2001, Requirement of chromomethylase3 for maintenance of cpxpg methylation, Science, 292, 2077, 10.1126/science.1059745

Laurent, 2010, Dynamic changes in the human methylome during differentiation, Genome Res., 20, 320, 10.1101/gr.101907.109

Lister, 2009, Human DNA methylomes at base resolution show widespread epigenomic differences, Nature, 462, 315, 10.1038/nature08514

Lister, 2013, Global epigenomic reconfiguration during mammalian brain development, Science, 341, 1237905, 10.1126/science.1237905

Gowher, 2001, Enzymatic properties of recombinant Dnmt3a DNA methyltransferase from mouse: The enzyme modifies DNA in a non-processive manner and also methylates non-CpG [correction of non-CpA] sites, J. Mol. Biol., 309, 1201, 10.1006/jmbi.2001.4710

Ramsahoye, 2000, Non-cpg methylation is prevalent in embryonic stem cells and may be mediated by DNA methyltransferase 3a, Proc. Natl. Acad. Sci. USA, 97, 5237, 10.1073/pnas.97.10.5237

Schofield, 2003, DNA mismatch repair: Molecular mechanisms and biological function, Ann. Rev. Microbiol., 57, 579, 10.1146/annurev.micro.57.030502.090847

Ito, 2011, Tet proteins can convert 5-methylcytosine to 5-formylcytosine and 5-carboxylcytosine, Science, 333, 1300, 10.1126/science.1210597

He, 2011, Tet-mediated formation of 5-carboxylcytosine and its excision by tdg in mammalian DNA, Science, 333, 1303, 10.1126/science.1210944

Mellen, 2012, MeCP2 binds to 5hmc enriched within active genes and accessible chromatin in the nervous system, Cell, 151, 1417, 10.1016/j.cell.2012.11.022

Berger, 2009, An operational definition of epigenetics, Genes Dev., 23, 781, 10.1101/gad.1787609

Law, 2010, Establishing, maintaining and modifying DNA methylation patterns in plants and animals, Nat. Rev. Genet., 11, 204, 10.1038/nrg2719

Jaenisch, 2003, Epigenetic regulation of gene expression: How the genome integrates intrinsic and environmental signals, Nat. Genet., 33, 245, 10.1038/ng1089

Smith, 2013, DNA methylation: Roles in mammalian development, Nat. Rev. Genet., 14, 204, 10.1038/nrg3354

Illingworth, R., Kerr, A., Desousa, D., Jorgensen, H., Ellis, P., Stalker, J., Jackson, D., Clee, C., Plumb, R., and Rogers, J. (2008). A novel CpG island set identifies tissue-specific methylation at developmental gene loci. PLoS Biol., 6.

Felsenfeld, 2014, A brief history of epigenetics, Cold Spring Harb. Perspect. Biol., 6, a018200, 10.1101/cshperspect.a018200

Yang, 2014, Gene body methylation can alter gene expression and is a therapeutic target in cancer, Cancer Cell, 26, 577, 10.1016/j.ccr.2014.07.028

Jones, 2012, Functions of DNA methylation: Islands, start sites, gene bodies and beyond, Nat. Rev. Genet., 13, 484, 10.1038/nrg3230

Chodavarapu, 2010, Relationship between nucleosome positioning and DNA methylation, Nature, 466, 388, 10.1038/nature09147

Shukla, 2011, Ctcf-promoted rna polymerase ii pausing links DNA methylation to splicing, Nature, 479, 74, 10.1038/nature10442

Irizarry, 2009, The human colon cancer methylome shows similar hypo- and hypermethylation at conserved tissue-specific CpG island shores, Nat. Genet., 41, 178, 10.1038/ng.298

Alisch, 2012, Age-associated DNA methylation in pediatric populations, Genome Res., 22, 623, 10.1101/gr.125187.111

Pirazzini, 2012, Space/population and time/age in DNA methylation variability in humans: A study on igf2/h19 locus in different italian populations and in mono- and di-zygotic twins of different age, Aging, 4, 509, 10.18632/aging.100476

Heyn, 2012, Distinct DNA methylomes of newborns and centenarians, Proc. Natl. Acad. Sci. USA, 109, 10522, 10.1073/pnas.1120658109

Shimoda, 2014, Decrease in cytosine methylation at CpG island shores and increase in DNA fragmentation during zebrafish aging, Age, 36, 103, 10.1007/s11357-013-9548-5

Yen, 1992, Isolation and characterization of the cdna encoding human DNA methyltransferase, Nucleic Acids Res., 20, 2287, 10.1093/nar/20.9.2287

Feng, 2009, The role of DNA methylation in the central nervous system and neuropsychiatric disorders, Int. Rev. Neurobiol., 89, 67, 10.1016/S0074-7742(09)89004-1

Chen, 2003, Derepression of Bdnf transcription involves calcium-dependent phosphorylation of MeCP2, Science, 302, 885, 10.1126/science.1086446

Tohgi, 1999, Reduction with age in methylcytosine in the promoter region -224 approximately -101 of the amyloid precursor protein gene in autopsy human cortex, Mol. Brain Res., 70, 288, 10.1016/S0169-328X(99)00163-1

Okano, 1998, Cloning and characterization of a family of novel mammalian DNA (cytosine-5) methyltransferases, Nat. Genet., 19, 219, 10.1038/890

Okano, 1999, DNA methyltransferases DNMT3A and DNMT3B are essential for de novo methylation and mammalian development, Cell, 99, 247, 10.1016/S0092-8674(00)81656-6

Klein, 2011, Mutations in dnmt1 cause hereditary sensory neuropathy with dementia and hearing loss, Nat. Genet., 43, 595, 10.1038/ng.830

Jurkowska, 2011, Structure and function of mammalian DNA methyltransferases, ChemBioChem, 12, 206, 10.1002/cbic.201000195

Goll, 2005, Eukaryotic cytosine methyltransferases, Ann. Rev. Biochem., 74, 481, 10.1146/annurev.biochem.74.010904.153721

Reik, 2001, Epigenetic reprogramming in mammalian development, Science, 293, 1089, 10.1126/science.1063443

Reik, 2007, Stability and flexibility of epigenetic gene regulation in mammalian development, Nature, 447, 425, 10.1038/nature05918

Patil, 2014, The evidence for functional non-CpG methylation in mammalian cells, Epigenetics, 9, 823, 10.4161/epi.28741

Ziller, M.J., Muller, F., Liao, J., Zhang, Y., Gu, H., Bock, C., Boyle, P., Epstein, C.B., Bernstein, B.E., and Lengauer, T. (2011). Genomic distribution and inter-sample variation of non-CpG methylation across human cell types. PLoS Genet., 7.

Barres, 2009, Non-cpg methylation of the PGC-1alpha promoter through dnmt3b controls mitochondrial density, Cell Metabol., 10, 189, 10.1016/j.cmet.2009.07.011

Lister, 2011, Hotspots of aberrant epigenomic reprogramming in human induced pluripotent stem cells, Nature, 471, 68, 10.1038/nature09798

Ma, 2014, Abnormalities in human pluripotent cells due to reprogramming mechanisms, Nature, 511, 177, 10.1038/nature13551

Guo, 2014, Distribution, recognition and regulation of non-CpG methylation in the adult mammalian brain, Nat. Neurosci., 17, 215, 10.1038/nn.3607

Barres, 2013, Weight loss after gastric bypass surgery in human obesity remodels promoter methylation, Cell Rep., 3, 1020, 10.1016/j.celrep.2013.03.018

Xie, 2012, Base-resolution analyses of sequence and parent-of-origin dependent DNA methylation in the mouse genome, Cell, 148, 816, 10.1016/j.cell.2011.12.035

Inoue, 2005, Effects of methylation of non-CpG sequence in the promoter region on the expression of human synaptotagmin XI (syt11), Gene, 348, 123, 10.1016/j.gene.2004.12.044

Guo, 2014, The DNA methylation landscape of human early embryos, Nature, 511, 606, 10.1038/nature13544

Tomizawa, 2011, Dynamic stage-specific changes in imprinted differentially methylated regions during early mammalian development and prevalence of non-CpG methylation in oocytes, Development, 138, 811, 10.1242/dev.061416

Varley, 2013, Dynamic DNA methylation across diverse human cell lines and tissues, Genome Res., 23, 555, 10.1101/gr.147942.112

Zvetkova, 2005, Global hypomethylation of the genome in XX embryonic stem cells, Nat. Genet., 37, 1274, 10.1038/ng1663

Arand, J., Spieler, D., Karius, T., Branco, M.R., Meilinger, D., Meissner, A., Jenuwein, T., Xu, G., Leonhardt, H., and Wolf, V. (2012). In vivo control of CpG and non-CpG DNA methylation by DNA methyltransferases. PLoS Genet., 8.

Ichiyanagi, 2013, Accumulation and loss of asymmetric non-CpG methylation during male germ-cell development, Nucleic Acids Res., 41, 738, 10.1093/nar/gks1117

Liao, 2015, Targeted disruption of DNMT1, DNMT3A and DNMT3B in human embryonic stem cells, Nat. Genet., 47, 469, 10.1038/ng.3258

Pevsner, 2007, DNA methylation signatures within the human brain, Am. J. Hum. Genet., 81, 1304, 10.1086/524110

Kozlenkov, 2016, Substantial DNA methylation differences between two major neuronal subtypes in human brain, Nucleic acids Res., 44, 2593, 10.1093/nar/gkv1304

Guo, 2011, Neuronal activity modifies the DNA methylation landscape in the adult brain, Nat. Neurosci., 14, 1345, 10.1038/nn.2900

Xie, 2013, Epigenomic analysis of multilineage differentiation of human embryonic stem cells, Cell, 153, 1134, 10.1016/j.cell.2013.04.022

Reubinoff, 2000, Embryonic stem cell lines from human blastocysts: Somatic differentiation in vitro, Nat. Biotechnol., 18, 399, 10.1038/74447

Zhang, 2001, In vitro differentiation of transplantable neural precursors from human embryonic stem cells, Nat. Biotechnol., 19, 1129, 10.1038/nbt1201-1129

He, 2015, Non-CG methylation in the human genome, Ann. Rev. Genom. Hum. Genet., 16, 55, 10.1146/annurev-genom-090413-025437

Kozlenkov, 2014, Differences in DNA methylation between human neuronal and glial cells are concentrated in enhancers and non-CpG sites, Nucleic Acids Res., 42, 109, 10.1093/nar/gkt838

Klose, 2006, Genomic DNA methylation: The mark and its mediators, Trends Biochem. Sci., 31, 89, 10.1016/j.tibs.2005.12.008

Shahbazian, 2002, Insight into rett syndrome: MeCP2 levels display tissue- and cell-specific differences and correlate with neuronal maturation, Hum. Mol. Genet., 11, 115, 10.1093/hmg/11.2.115

Guy, 2011, The role of MeCP2 in the brain, Ann. Rev. Cell Dev. Biol., 27, 631, 10.1146/annurev-cellbio-092910-154121

Kishi, 2004, MeCP2 is progressively expressed in post-migratory neurons and is involved in neuronal maturation rather than cell fate decisions, Mol. Cell. Neurosci., 27, 306, 10.1016/j.mcn.2004.07.006

Skene, 2010, Neuronal MeCP2 is expressed at near histone-octamer levels and globally alters the chromatin state, Mol. Cell, 37, 457, 10.1016/j.molcel.2010.01.030

Nan, 1998, Transcriptional repression by the methyl-cpg-binding protein MeCP2 involves a histone deacetylase complex, Nature, 393, 386, 10.1038/30764

Jones, 1998, Methylated DNA and MeCP2 recruit histone deacetylase to repress transcription, Nat. Genet., 19, 187, 10.1038/561

Kriaucionis, 2009, The nuclear DNA base 5-hydroxymethylcytosine is present in purkinje neurons and the brain, Science, 324, 929, 10.1126/science.1169786

Globisch, D., Munzel, M., Muller, M., Michalakis, S., Wagner, M., Koch, S., Bruckl, T., Biel, M., and Carell, T. (2010). Tissue distribution of 5-hydroxymethylcytosine and search for active demethylation intermediates. PLoS ONE, 5.

Munzel, 2010, Quantification of the sixth DNA base hydroxymethylcytosine in the brain, Angew. Chem., 49, 5375, 10.1002/anie.201002033

Song, 2011, Selective chemical labeling reveals the genome-wide distribution of 5-hydroxymethylcytosine, Nat. Biotechnol., 29, 68, 10.1038/nbt.1732

Dawlaty, 2011, TET1 is dispensable for maintaining pluripotency and its loss is compatible with embryonic and postnatal development, Cell Stem Cell, 9, 166, 10.1016/j.stem.2011.07.010

Hahn, 2013, Dynamics of 5-hydroxymethylcytosine and chromatin marks in mammalian neurogenesis, Cell Rep., 3, 291, 10.1016/j.celrep.2013.01.011

Zhang, 2013, TET1 regulates adult hippocampal neurogenesis and cognition, Cell Stem Cell, 13, 237, 10.1016/j.stem.2013.05.006

Li, 2015, Critical role of tet3 in neural progenitor cell maintenance and terminal differentiation, Mol. Neurobiol., 51, 142, 10.1007/s12035-014-8734-5

Szwagierczak, 2010, Sensitive enzymatic quantification of 5-hydroxymethylcytosine in genomic DNA, Nucleic Acids Res., 38, e181, 10.1093/nar/gkq684

Szulwach, K.E., Li, X., Li, Y., Song, C.X., Han, J.W., Kim, S., Namburi, S., Hermetz, K., Kim, J.J., and Rudd, M.K. (2011). Integrating 5-hydroxymethylcytosine into the epigenomic landscape of human embryonic stem cells. PLoS Genet., 7.

Ruzov, 2011, Lineage-specific distribution of high levels of genomic 5-hydroxymethylcytosine in mammalian development, Cell Res., 21, 1332, 10.1038/cr.2011.113

Tan, 2013, Genome-wide comparison of DNA hydroxymethylation in mouse embryonic stem cells and neural progenitor cells by a new comparative hmedip-seq method, Nucleic Acids Res., 41, e84, 10.1093/nar/gkt091

Colquitt, 2013, Alteration of genic 5-hydroxymethylcytosine patterning in olfactory neurons correlates with changes in gene expression and cell identity, Proc. Natl. Acad. Sci. USA, 110, 14682, 10.1073/pnas.1302759110

Gan, 2013, Dynamics of 5-hydroxymethylcytosine during mouse spermatogenesis, Nat. Commun., 4, 1995, 10.1038/ncomms2995

Wen, 2014, Whole-genome analysis of 5-hydroxymethylcytosine and 5-methylcytosine at base resolution in the human brain, Genome Biol., 15, R49, 10.1186/gb-2014-15-3-r49

Gabel, 2015, Disruption of DNA-methylation-dependent long gene repression in rett syndrome, Nature, 522, 89, 10.1038/nature14319

Spruijt, 2013, Dynamic readers for 5-(hydroxy)methylcytosine and its oxidized derivatives, Cell, 152, 1146, 10.1016/j.cell.2013.02.004

Minor, 2013, Ascorbate induces ten-eleven translocation (TET) methylcytosine dioxygenase-mediated generation of 5-hydroxymethylcytosine, J. Biol. Chem., 288, 13669, 10.1074/jbc.C113.464800

Spector, 2014, The nexus of vitamin homeostasis and DNA synthesis and modification in mammalian brain, Mol. Brain, 7, 3, 10.1186/1756-6606-7-3

Sherwani, 2015, Role of 5-hydroxymethylcytosine in neurodegeneration, Gene, 570, 17, 10.1016/j.gene.2015.06.052

Wheldon, 2014, Transient accumulation of 5-carboxylcytosine indicates involvement of active demethylation in lineage specification of neural stem cells, Cell Rep., 7, 1353, 10.1016/j.celrep.2014.05.003

Miller, 2007, Covalent modification of DNA regulates memory formation, Neuron, 53, 857, 10.1016/j.neuron.2007.02.022

Schanen, 2006, Epigenetics of autism spectrum disorders, Hum. Mol. Genet., 15, R138, 10.1093/hmg/ddl213

LaSalle, 2009, Evolving role of MeCP2 in rett syndrome and autism, Epigenomics, 1, 119, 10.2217/epi.09.13

Nicolia, 2017, DNA methylation profiles of selected pro-inflammatory cytokines in alzheimer disease, J. Neuropathol. Exp. Neurol., 76, 27

Bird, 2002, DNA methylation patterns and epigenetic memory, Genes Dev., 16, 6, 10.1101/gad.947102

Robertson, 2000, DNA methylation in health and disease, Nat. Rev. Genet., 1, 11, 10.1038/35049533

Urdinguio, 2009, Epigenetic mechanisms in neurological diseases: Genes, syndromes, and therapies, Lancet Neurol., 8, 1056, 10.1016/S1474-4422(09)70262-5

Iqbal, 2008, Alzheimer neurofibrillary degeneration: Significance, etiopathogenesis, therapeutics and prevention, J. Cell. Mol. Med., 12, 38, 10.1111/j.1582-4934.2008.00225.x

Aso, 2013, DNA methylation map of mouse and human brain identifies target genes in Alzheimer’s disease, Brain, 136, 3018, 10.1093/brain/awt237

Blanch, 2016, Altered mitochondrial DNA methylation pattern in Alzheimer disease-related pathology and in parkinson disease, Am. J. Pathol., 186, 385, 10.1016/j.ajpath.2015.10.004

Liu, 2016, Cpg methylation patterns of human mitochondrial DNA, Sci. Rep., 6, 23421, 10.1038/srep23421

Chouliaras, 2013, Consistent decrease in global DNA methylation and hydroxymethylation in the hippocampus of Alzheimer’s disease patients, Neurobiol. Aging, 34, 2091, 10.1016/j.neurobiolaging.2013.02.021

Condliffe, 2014, Cross-region reduction in 5-hydroxymethylcytosine in alzheimer’s disease brain, Neurobiol. Aging, 35, 1850, 10.1016/j.neurobiolaging.2014.02.002

Coppieters, 2014, Global changes in DNA methylation and hydroxymethylation in Alzheimer’s disease human brain, Neurobiol. Aging, 35, 1334, 10.1016/j.neurobiolaging.2013.11.031

Lovell, 2013, Epigenetic changes in the progression of Alzheimer’s disease, Mech. Ageing Dev., 134, 486, 10.1016/j.mad.2013.08.005

Hagberg, 1985, Rett’s syndrome: Prevalence and impact on progressive severe mental retardation in girls, Acta Paediatr. Scand., 74, 405, 10.1111/j.1651-2227.1985.tb10993.x

Rett, 1966, On a unusual brain atrophy syndrome in hyperammonemia in childhood, Wiener Medizinische Wochenschrift, Volume 116, 723

Martinowich, 2003, DNA methylation-related chromatin remodeling in activity-dependent BDNF gene regulation, Science, 302, 890, 10.1126/science.1090842

Nuber, 2005, Up-regulation of glucocorticoid-regulated genes in a mouse model of Rett syndrome, Hum. Mol. Genet., 14, 2247, 10.1093/hmg/ddi229

Horike, 2005, Loss of silent-chromatin looping and impaired imprinting of Dlx5 in Rett syndrome, Nat. Genet., 37, 31, 10.1038/ng1491

Klose, 2005, DNA binding selectivity of MeCP2 due to a requirement for A/T sequences adjacent to methyl-CpG, Mol. Cell, 19, 667, 10.1016/j.molcel.2005.07.021

Makedonski, 2005, MeCP2 deficiency in Rett syndrome causes epigenetic aberrations at the PWS/AS imprinting center that affects UBE3A expression, Hum. Mol. Genet., 14, 1049, 10.1093/hmg/ddi097

Amir, 1999, Rett syndrome is caused by mutations in X-linked MeCP2, encoding methyl-CpG-binding protein 2, Nat. Genet., 23, 185, 10.1038/13810

Chen, 2015, MeCP2 binds to non-CG methylated DNA as neurons mature, influencing transcription and the timing of onset for Rett syndrome, Proc. Natl. Acad. Sci. USA, 112, 5509, 10.1073/pnas.1505909112

Irwin, 2000, Dendritic spine structural anomalies in fragile-X mental retardation syndrome, Cereb. Cortex, 10, 1038, 10.1093/cercor/10.10.1038

Huber, 2002, Altered synaptic plasticity in a mouse model of fragile X mental retardation, Proc. Natl. Acad. Sci. USA, 99, 7746, 10.1073/pnas.122205699

Garber, 2008, Fragile X syndrome, Eur. J. Hum. Genet., 16, 666, 10.1038/ejhg.2008.61

Mostofsky, 1998, Decreased cerebellar posterior vermis size in fragile X syndrome: Correlation with neurocognitive performance, Neurology, 50, 121, 10.1212/WNL.50.1.121

Nolin, 1996, Familial transmission of the FMR1 CgG repeat, Am. J. Hum. Genet., 59, 1252

Kremer, 1991, Mapping of DNA instability at the fragile x to a trinucleotide repeat sequence p (CcG) n, Science, 252, 1711, 10.1126/science.1675488

Oberle, 1991, Instability of a 550-base pair DNA segment and abnormal methylation in fragile x syndrome, Science, 252, 1097, 10.1126/science.252.5009.1097

Coffee, 1999, Acetylated histones are associated with fmr1 in normal but not fragile X-syndrome cells, Nat. Genet., 22, 98, 10.1038/8807

Tabolacci, E., Palumbo, F., Nobile, V., and Neri, G. (2016). Transcriptional reactivation of the fmr1 gene. A possible approach to the treatment of the fragile X syndrome. Genes, 7.

Lees, 2009, Parkinson’s disease, Lancet, 373, 2055, 10.1016/S0140-6736(09)60492-X

Volta, 2015, Insights from late-onset familial parkinsonism on the pathogenesis of idiopathic parkinson’s disease, Lancet Neurol., 14, 1054, 10.1016/S1474-4422(15)00186-6

Grundemann, 2008, Elevated alpha-synuclein mrna levels in individual UV-laser-microdissected dopaminergic substantia nigra neurons in idiopathic parkinson’s disease, Nucleic Acids Res., 36, e38, 10.1093/nar/gkn084

Schmitt, 2015, L-dopa increases alpha-synuclein DNA methylation in parkinson’s disease patients in vivo and in vitro, Mov. Disord., 30, 1794, 10.1002/mds.26319

Zhang, 2016, Reduced plasma taurine level in parkinson’s disease: Association with motor severity and levodopa treatment, Int. J. Neurosci., 126, 630

Desplats, 2011, Alpha-synuclein sequesters DNMT1 from the nucleus: A novel mechanism for epigenetic alterations in lewy body diseases, J. Biol. Chem., 286, 9031, 10.1074/jbc.C110.212589

Carvey, 2005, Intra-parenchymal injection of tumor necrosis factor-alpha and interleukin 1-beta produces dopamine neuron loss in the rat, J. Neural Transm., 112, 601, 10.1007/s00702-004-0222-z

Pieper, 2008, Different methylation of the tnf-alpha promoter in cortex and substantia nigra: Implications for selective neuronal vulnerability, Neurobiol. Dis., 32, 521, 10.1016/j.nbd.2008.09.010

Pringsheim, 2012, The incidence and prevalence of Huntington’s disease: A systematic review and meta-analysis, Mov. Disord., 27, 1083, 10.1002/mds.25075

MacDonald, 1993, A novel gene containing a trinucleotide repeat that is expanded and unstable on huntington’s disease chromosomes, Cell, 72, 971, 10.1016/0092-8674(93)90585-E

Kremer, 1994, A worldwide study of the Huntington’s disease mutation: The sensitivity and specificity of measuring cag repeats, N. Engl. J. Med., 330, 1401, 10.1056/NEJM199405193302001

Islam, 2016, DNA methylation profiling in human Huntington’s disease brain, Hum. Mol. Genet., 25, 2013, 10.1093/hmg/ddw076

Blanch, 2013, Increased 5-methylcytosine and decreased 5-hydroxymethylcytosine levels are associated with reduced striatal A2AR levels in Huntington’s disease, Neuromol. Med., 15, 295, 10.1007/s12017-013-8219-0

Thomas, 2013, A novel method for detecting 7-methyl guanine reveals aberrant methylation levels in Huntington disease, Anal. Biochem., 436, 112, 10.1016/j.ab.2013.01.035

Wang, 2013, Genome-wide loss of 5-hmC is a novel epigenetic feature of Huntington’s disease, Hum. Mol. Genet., 22, 3641, 10.1093/hmg/ddt214

Bai, 2014, Epigenetic dysregulation of hairy and enhancer of split 4 (HES4) is associated with striatal degeneration in postmortem Huntington brains, Hum. Mol. Genet., 24, 1441, 10.1093/hmg/ddu561

McFarland, 2014, MeCP2: A novel huntingtin interactor, Hum. Mol. Genet., 23, 1036, 10.1093/hmg/ddt499

Rowland, 2001, Amyotrophic lateral sclerosis, N. Engl. J. Med., 344, 1688, 10.1056/NEJM200105313442207

Heath, 2002, Update on the glutamatergic neurotransmitter system and the role of excitotoxicity in amyotrophic lateral sclerosis, Muscle Nerv., 26, 438, 10.1002/mus.10186

Martin, 2010, Mitochondrial and cell death mechanisms in neurodegenerative diseases, Pharmaceuticals, 3, 839, 10.3390/ph3040839

Martin, 2013, Aberrant regulation of DNA methylation in amyotrophic lateral sclerosis: A new target of disease mechanisms, Neurotherapeutics, 10, 722, 10.1007/s13311-013-0205-6

Swash, 2011, Amyotrophic lateral sclerosis: An update, Curr. Opin. Neurol., 24, 497, 10.1097/WCO.0b013e32834916a9

Figueroa-Romero, C., Hur, J., Bender, D.E., Delaney, C.E., Cataldo, M.D., Smith, A.L., Yung, R., Ruden, D.M., Callaghan, B.C., and Feldman, E.L. (2012). Identification of epigenetically altered genes in sporadic amyotrophic lateral sclerosis. PLoS ONE, 7.

Chestnut, 2011, Epigenetic regulation of motor neuron cell death through DNA methylation, J. Neurosci., 31, 16619, 10.1523/JNEUROSCI.1639-11.2011

Bollati, 2011, DNA methylation in repetitive elements and alzheimer disease, Brain Behav. Immun., 25, 1078, 10.1016/j.bbi.2011.01.017

Sakowski, 2015, Amyotrophic lateral sclerosis: Mechanisms and therapeutics in the epigenomic era, Nat. Rev. Neurol., 11, 266, 10.1038/nrneurol.2015.57

Mackenzie, 2011, Expanded GGGGCC hexanucleotide repeat in noncoding region of C9orf72 causes chromosome 9p-linked FTD and ALS, Neuron, 72, 245, 10.1016/j.neuron.2011.09.011

Xi, 2013, Hypermethylation of the CpG island near the G 4 C 2 repeat in ALS with A C9orf72 expansion, Am. J. Hum. Genet., 92, 981, 10.1016/j.ajhg.2013.04.017

Xi, 2015, The C9orf72 repeat expansion itself is methylated in ALS and FTLD patients, Acta Neuropathol., 129, 715, 10.1007/s00401-015-1401-8

Ciura, 2013, Loss of function of C9orf72 causes motor deficits in a zebrafish model of amyotrophic lateral sclerosis, Ann. Neurol., 74, 180, 10.1002/ana.23946

Bauer, 2016, Methylation of C9orf72 expansion reduces rna foci formation and dipeptide-repeat proteins expression in cells, Neurosci. Lett., 612, 204, 10.1016/j.neulet.2015.12.018

Day, 2015, DNA methylation slows effects of C9orf72 mutations an epigenetic brake on genetic inheritance, Neurology, 84, 1616, 10.1212/WNL.0000000000001504

Pihlstrom, 2015, Parkinson’s disease correlates with promoter methylation in the alpha-synuclein gene, Mov. Disord., 30, 577, 10.1002/mds.26073

Masliah, 2013, Distinctive patterns of DNA methylation associated with parkinson disease: Identification of concordant epigenetic changes in brain and peripheral blood leukocytes, Epigenetics, 8, 1030, 10.4161/epi.25865

Lancaster, 2013, Cerebral organoids model human brain development and microcephaly, Nature, 501, 373, 10.1038/nature12517

Mariani, 2015, Foxg1-dependent dysregulation of gaba/glutamate neuron differentiation in autism spectrum disorders, Cell, 162, 375, 10.1016/j.cell.2015.06.034