PRDM8 internal promoter hyperhydroxymethylation correlates with increased expression of the corresponding transcript in Down syndrome

Lu,Zhaoning; Liu,Yanna; Ren,Zhaorui; Yan,Jingbin

doi:10.3892/mmr.2016.5375

PRDM8 internal promoter hyperhydroxymethylation correlates with increased expression of the corresponding transcript in Down syndrome

Authors:
- Zhaoning Lu
- Yanna Liu
- Zhaorui Ren
- Jingbin Yan
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Affiliations: Shanghai Institute of Medical Genetics, Shanghai Children's Hospital, Shanghai Jiao Tong University, Shanghai 200040, P.R. China
Published online on: June 8, 2016 https://doi.org/10.3892/mmr.2016.5375
Pages: 1227-1234

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Abstract

Down syndrome (DS) is the most common form of intellectual disability associated with central nervous system abnormalities and results from an extra complete or partial copy of human chromosome 21. However, whether DNA hydroxymethylation is perturbed in a specific gene associated with DS phenotypes, or the alteration of DNA hydroxymethylation results in changes of gene expression in DS remains unidentified. The current study mapped 5‑methylcytosine and 5‑hydroxymethylcytosine at CpG islands of the PR domain containing 8 (PRDM8) in the peripheral blood of 16 DS and 19 normal samples by oxidative bisulfite-pyrosequencing. Furthermore, the association of the expression levels of the two transcripts and epigenetic modification in different genomic contexts of PRDM8 was analyzed. The results demonstrated hypermethylation and hyperhydroxymethylation at the internal promoter of PRDM8 in DS, and significantly increased the expression of PRDM8 transcript variant 2 in the DS patients (median 3.9 vs. 2.04; P=0.016), accompanied by a positive correlation between the expression of two PRDM8 transcripts and hydroxymethylation at the corresponding external and internal promoters in patients, although not in the controls. A similar association was observed between the expression of transcript variant 1 and intragenic methylation of PRDM8. Taken together, the results of the present study suggest a critical role for DNA hydroxymethylation and methylation in regulating abnormal PRDM8 overexpression in DS.

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1	Dierssen M: Down syndrome: The brain in trisomic mode. Nat Rev Neurosci. 13:844–858. 2012. View Article : Google Scholar : PubMed/NCBI
2	Haydar TF and Reeves RH: Trisomy 21 and early brain development. Trends Neurosci. 35:81–91. 2012. View Article : Google Scholar
3	Letourneau A, Santoni FA, Bonilla X, Sailani MR, Gonzalez D, Kind J, Chevalier C, Thurman R, Sandstrom RS, Hibaoui Y, et al: Domains of genome-wide gene expression dysregulation in Down's syndrome. Nature. 508:345–350. 2014. View Article : Google Scholar : PubMed/NCBI
4	Lockstone HE, Harris LW, Swatton JE, Wayland MT, Holland AJ and Bahn S: Gene expression profiling in the adult Down syndrome brain. Genomics. 90:647–660. 2007. View Article : Google Scholar : PubMed/NCBI
5	Rozek LS, Dolinoy DC, Sartor MA and Omenn GS: Epigenetics: Relevance and implications for public health. Annu Rev Public Health. 35:105–122. 2014. View Article : Google Scholar : PubMed/NCBI
6	Kerkel K, Schupf N, Hatta K, Pang D, Salas M, Kratz A, Minden M, Murty V, Zigman WB, Mayeux RP, et al: Altered DNA methylation in leukocytes with trisomy 21. PLoS Genet. 6:e10012122010. View Article : Google Scholar : PubMed/NCBI
7	Jin S, Lee YK, Lim YC, Zheng Z, Lin XM, Ng DP, Holbrook JD, Law HY, Kwek KY, Yeo GS, et al: Global DNA hypermethylation in down syndrome placenta. PLoS Genet. 9:e10035152013. View Article : Google Scholar : PubMed/NCBI
8	Inoue M, Kuroda T, Honda A, Komabayashi-Suzuki M, Komai T, Shinkai Y and Mizutani K: Prdm8 regulates the morphological transition at multipolar phase during neocortical development. PLoS One. 9:e863562014. View Article : Google Scholar : PubMed/NCBI
9	Ross SE, McCord AE, Jung C, Atan D, Mok SI, Hemberg M, Kim TK, Salogiannis J, Hu L, Cohen S, et al: Bhlhb5 and Prdm8 form a repressor complex involved in neuronal circuit assembly. Neuron. 73:292–303. 2012. View Article : Google Scholar : PubMed/NCBI
10	Tsagaratou A, Äijö T, Lio CW, Yue X, Huang Y, Jacobsen SE, Lähdesmäki H and Rao A: Dissecting the dynamic changes of 5-hydroxymethylcytosine in T-cell development and differentiation. Proc Natl Acad Sci USA. 111:E3306–3315. 2014. View Article : Google Scholar : PubMed/NCBI
11	Tahiliani M, Koh KP, Shen Y, Pastor WA, Bandukwala H, Brudno Y, Agarwal S, Iyer LM, Liu DR, Aravind L, et al: Conversion of 5-methylcytosine to 5-hydroxymethylcytosine in mammalian DNA by MLL partner TET1. Science. 324:930–935. 2009. View Article : Google Scholar : PubMed/NCBI
12	Ito S, Shen L, Dai Q, Wu SC, Collins LB, Swenberg JA, He C and Zhang Y: Tet proteins can convert 5-methylcytosine to 5-formyl-cytosine and 5-carboxylcytosine. Science. 333:1300–1303. 2011. View Article : Google Scholar : PubMed/NCBI
13	Wu H and Zhang Y: Reversing DNA methylation: Mechanisms, genomics, and biological functions. Cell. 156:45–68. 2014. View Article : Google Scholar : PubMed/NCBI
14	Li X, Wei W, Zhao QY, Widagdo J, Baker-Andresen D, Flavell CR, D'Alessio A, Zhang Y and Bredy TW: Neocortical Tet3-mediated accumulation of 5-hydroxymethylcytosine promotes rapid behavioral adaptation. Proc Natl Acad Sci USA. 111:7120–7125. 2014. View Article : Google Scholar : PubMed/NCBI
15	Mikeska T, Felsberg J, Hewitt CA and Dobrovic A: Analysing DNA methylation using bisulphite pyrosequencing. Methods Mol Biol. 791:33–53. 2011. View Article : Google Scholar : PubMed/NCBI
16	Booth MJ, Ost TW, Beraldi D, Bell NM, Branco MR, Reik W and Balasubramanian S: Oxidative bisulfite sequencing of 5-methylcytosine and 5-hydroxymethylcytosine. Nat Protoc. 8:1841–1851. 2013. View Article : Google Scholar : PubMed/NCBI
17	Booth MJ, Branco MR, Ficz G, Oxley D, Krueger F, Reik W and Balasubramanian S: Quantitative sequencing of 5-methyl-cytosine and 5-hydroxymethylcytosine at single-base resolution. Science. 336:934–937. 2012. View Article : Google Scholar : PubMed/NCBI
18	Livak KJ and Schmittgen TD: Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) Method. Methods. 25:402–408. 2001. View Article : Google Scholar
19	Huang Y, Pastor WA, Shen Y, Tahiliani M, Liu DR and Rao A: The behaviour of 5-hydroxymethylcytosine in bisulfite sequencing. PLoS One. 5:e88882010. View Article : Google Scholar : PubMed/NCBI
20	Pastor WA, Aravind L and Rao A: TETonic shift: Biological roles of TET proteins in DNA demethylation and transcription. Nat Rev Mol Cell Biol. 14:341–356. 2013. View Article : Google Scholar : PubMed/NCBI
21	Stroud H, Feng S, Morey Kinney S, Pradhan S and Jacobsen SE: 5-Hydroxymethylcytosine is associated with enhancers and gene bodies in human embryonic stem cells. Genome Biol. 12:R542011. View Article : Google Scholar : PubMed/NCBI
22	Huang Y, Chavez L, Chang X, Wang X, Pastor WA, Kang J, Zepeda-Martínez JA, Pape UJ, Jacobsen SE, Peters B, et al: Distinct roles of the methylcytosine oxidases Tet1 and Tet2 in mouse embryonic stem cells. Proc Natl Acad Sci USA. 111:1361–1366. 2014. View Article : Google Scholar : PubMed/NCBI
23	Wu H, D'Alessio AC, Ito S, Wang Z, Cui K, Zhao K, Sun YE and Zhang Y: Genome-wide analysis of 5-hydroxymethylcy-tosine distribution reveals its dual function in transcriptional regulation in mouse embryonic stem cells. Genes Dev. 25:679–684. 2011. View Article : Google Scholar : PubMed/NCBI
24	Szulwach KE, Li X, Li Y, Song CX, Han JW, Kim S, Namburi S, Hermetz K, Kim JJ, Rudd MK, et al: Integrating 5-hydroxymethylcytosine into the epigenomic landscape of human embryonic stem cells. PLoS Genet. 7:e10021542011. View Article : Google Scholar : PubMed/NCBI
25	Colquitt BM, Allen WE, Barnea G and Lomvardas S: Alteration of genic 5-hydroxymethylcytosine patterning in olfactory neurons correlates with changes in gene expression and cell identity. Proc Natl Acad Sci USA. 110:14682–14687. 2013. View Article : Google Scholar : PubMed/NCBI
26	Wen L, Li X, Yan L, Tan Y, Li R, Zhao Y, Wang Y, Xie J, Zhang Y, Song C, et al: Whole-genome analysis of 5-hydroxy-methylcytosine and 5-methylcytosine at base resolution in the human brain. Genome Biol. 15:R492014. View Article : Google Scholar
27	Gan H, Wen L, Liao S, Lin X, Ma T, Liu J, Song CX, Wang M, He C, Han C, et al: Dynamics of 5-hydroxymethylcytosine during mouse spermatogenesis. Nat Commun. 4:19952013. View Article : Google Scholar : PubMed/NCBI
28	Jin SG, Wu X, Li AX and Pfeifer GP: Genomic mapping of 5-hydroxymethylcytosine in the human brain. Nucleic Acids Res. 39:5015–5024. 2011. View Article : Google Scholar : PubMed/NCBI
29	Jones PA: Functions of DNA methylation: Islands, start sites, gene bodies and beyond. Nat Rev Genet. 13:484–492. 2012. View Article : Google Scholar : PubMed/NCBI
30	Ball MP, Li JB, Gao Y, Lee JH, LeProust EM, Park IH, Xie B, Daley GQ and Church GM: Targeted and genome-scale strategies reveal gene-body methylation signatures in human cells. Nat Biotechnol. 27:361–368. 2009. View Article : Google Scholar : PubMed/NCBI
31	Aran D, Toperoff G, Rosenberg M and Hellman A: Replication timing-related and gene body-specific methylation of active human genes. Hum Mol Genet. 20:670–680. 2011. View Article : Google Scholar