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Open Access 01-12-2016 | Research article

Genome-wide DNA methylation analysis of transient neonatal diabetes type 1 patients with mutations in ZFP57

Authors: Mads Bak, Susanne E. Boonen, Christina Dahl, Johanne M. D. Hahnemann, Deborah J. D. G. Mackay, Zeynep Tümer, Karen Grønskov, I. Karen Temple, Per Guldberg, Niels Tommerup

Published in: BMC Medical Genetics | Issue 1/2016

Abstract

Background

Transient neonatal diabetes mellitus 1 (TNDM1) is a rare imprinting disorder characterized by intrautering growth retardation and diabetes mellitus usually presenting within the first six weeks of life and resolves by the age of 18 months. However, patients have an increased risk of developing diabetes mellitus type 2 later in life. Transient neonatal diabetes mellitus 1 is caused by overexpression of the maternally imprinted genes PLAGL1 and HYMAI on chromosome 6q24. One of the mechanisms leading to overexpression of the locus is hypomethylation of the maternal allele of PLAGL1 and HYMAI. A subset of patients with maternal hypomethylation at PLAGL1 have hypomethylation at additional imprinted loci throughout the genome, including GRB10, ZIM2 (PEG3), MEST (PEG1), KCNQ1OT1 and NESPAS (GNAS-AS1). About half of the TNDM1 patients carry mutations in ZFP57, a transcription factor involved in establishment and maintenance of methylation of imprinted loci. Our objective was to investigate whether additional regions are aberrantly methylated in ZFP57 mutation carriers.

Methods

Genome-wide DNA methylation analysis was performed on four individuals with homozygous or compound heterozygous ZFP57 mutations, three relatives with heterozygous ZFP57 mutations and five controls. Methylation status of selected regions showing aberrant methylation in the patients was verified using bisulfite-sequencing.

Results

We found large variability among the patients concerning the number and identity of the differentially methylated regions, but more than 60 regions were aberrantly methylated in two or more patients and a novel region within PPP1R13L was found to be hypomethylated in all the patients. The hypomethylated regions in common between the patients are enriched for the ZFP57 DNA binding motif.

Conclusions

We have expanded the epimutational spectrum of TNDM1 associated with ZFP57 mutations and found one novel region within PPP1R13L which is hypomethylated in all TNDM1 patients included in this study. Functional studies of the locus might provide further insight into the etiology of the disease.

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Biliya S, Bulla LA. Genomic imprinting: the influence of differential methylation in the two sexes. Exp Biol Med (Maywood). 2010;235:139–47.CrossRef

Delaval K, Feil R. Epigenetic regulation of mammalian genomic imprinting. Curr Opin Genet Dev. 2004;14:188–95.CrossRefPubMed

Mackay DJG, Temple IK. Transient neonatal diabetes mellitus type 1. Am J Med Genet C Semin Med Genet. 2010;154C:335–42.CrossRefPubMed

Mackay DJG, Callaway JLA, Marks SM, White HE, Acerini CL, Boonen SE, Dayanikli P, Firth H V, Goodship JA, Haemers AP, Hahnemann JMD, Kordonouri O, Masoud AF, Oestergaard E, Storr J, Ellard S, Hattersley AT, Robinson DO, Temple IK. Hypomethylation of multiple imprinted loci in individuals with transient neonatal diabetes is associated with mutations in ZFP57. Nat Genet. 2008;40:949–51.CrossRefPubMed

Boonen SE, Mackay DJG, Hahnemann JMD, Docherty L, Grønskov K, Lehmann A, Larsen LG, Haemers AP, Kockaerts Y, Dooms L, Vu DC, Ngoc CTB, Nguyen PB, Kordonouri O, Sundberg F, Dayanikli P, Puthi V, Acerini C, Massoud AF, Tümer Z, Temple IK. Transient neonatal diabetes, ZFP57, and hypomethylation of multiple imprinted loci: a detailed follow-up. Diabetes Care. 2013;36:505–12.CrossRefPubMedPubMedCentral

Li X, Ito M, Zhou F, Youngson N, Zuo X, Leder P, Ferguson-Smith AC. A maternal-zygotic effect gene, Zfp57, maintains both maternal and paternal imprints. Dev Cell. 2008;15:547–57.CrossRefPubMedPubMedCentral

Quenneville S, Verde G, Corsinotti A, Kapopoulou A, Jakobsson J, Offner S, Baglivo I, Pedone P V., Grimaldi G, Riccio A, Trono D. In embryonic stem cells, ZFP57/KAP1 recognize a methylated hexanucleotide to affect chromatin and DNA methylation of imprinting control regions. Mol Cell. 2011;44:361–72.CrossRefPubMedPubMedCentral

Baglivo I, Esposito S, De Cesare L, Sparago A, Anvar Z, Riso V, Cammisa M, Fattorusso R, Grimaldi G, Riccio A, Pedone PV. Genetic and epigenetic mutations affect the DNA binding capability of human ZFP57 in transient neonatal diabetes type 1. FEBS Lett. 2013;587:1474–81.CrossRefPubMedPubMedCentral

Docherty LE, Rezwan FI, Poole RL, Jagoe H, Lake H, Lockett GA, Arshad H, Wilson DI, Holloway JW, Temple IK, Mackay DJG. Genome-wide DNA methylation analysis of patients with imprinting disorders identifies differentially methylated regions associated with novel candidate imprinted genes. J Med Genet. 2014;51:229–38.CrossRefPubMedPubMedCentral

10.

Court F, Martin-Trujillo A, Romanelli V, Garin I, Iglesias-Platas I, Salafsky I, Guitart M, Perez de Nanclares G, Lapunzina P, Monk D. Genome-wide allelic methylation analysis reveals disease-specific susceptibility to multiple methylation defects in imprinting syndromes. Hum Mutat. 2013;34:595–602.PubMed

11.

Martin-Subero JI, Bibikova M, Mackay D, Wickham-Garcia E, Sellami N, Richter J, Santer R, Caliebe A, Fan J-B, Temple IK, Siebert R. Microarray-based DNA methylation analysis of imprinted loci in a patient with transient neonatal diabetes mellitus. Am J Med Genet A. 2008;146A:3227–9.CrossRefPubMed

12.

Li H, Durbin R. Fast and accurate short read alignment with Burrows-Wheeler transform. Bioinformatics. 2009;25:1754–60.CrossRefPubMedPubMedCentral

13.

Zhang Y, Liu T, Meyer CA, Eeckhoute J, Johnson DS, Bernstein BE, Nussbaum C, Myers RM, Brown M, Li W, Liu XS. Model-based analysis of ChIP-Seq (MACS). Genome Biol. 2008;9:R137.CrossRefPubMedPubMedCentral

14.

Robinson MD, McCarthy DJ, Smyth GK. edgeR: A Bioconductor package for differential expression analysis of digital gene expression data. Bioinformatics. 2009;26:139–40.CrossRefPubMedPubMedCentral

15.

Lan X, Adams C, Landers M, Dudas M, Krissinger D, Marnellos G, et al. High resolution detection and analysis of CpG dinucleotides methylation using MBD-seq technology. PLoS One. 2011;6.

16.

Krueger F, Andrews SR. Bismark: a flexible aligner and methylation caller for Bisulfite-Seq applications. Bioinformatics. 2011;27:1571–2.CrossRefPubMedPubMedCentral

17.

Serre D, Lee BH, Ting AH. MBD-isolated Genome Sequencing provides a high-throughput and comprehensive survey of DNA methylation in the human genome. Nucleic Acids Res. 2010;38:391–9.CrossRefPubMedPubMedCentral

18.

Bergamaschi D, Samuels Y, O’Neil NJ, Trigiante G, Crook T, Hsieh J-K, O’Connor DJ, Zhong S, Campargue I, Tomlinson ML, Kuwabara PE, Lu X. iASPP oncoprotein is a key inhibitor of p53 conserved from worm to human. Nat Genet. 2003;33:162–7.CrossRefPubMed

19.

Zhang X, Wang M, Zhou C, Chen S, Wang J. The expression of iASPP in acute leukemias. Leuk Res. 2005;29:179–83.CrossRefPubMed

20.

Jiang L, Siu MKY, Wong OGW, Tam KF, Lu X, Lam EWF, Ngan HYS, Le XF, Wong ESY, Monteiro LJ, Chan HY, Cheung ANY. iASPP and chemoresistance in ovarian cancers: effects on paclitaxel-mediated mitotic catastrophe. Clin Cancer Res. 2011;17:6924–33.CrossRefPubMed

21.

Liu Z, Zhang X, Huang D, Liu Y, Zhang X, Liu L, Li G, Dai Y, Tan H, Xiao J, Tian Y. Elevated expression of iASPP in head and neck squamous cell carcinoma and its clinical significance. Med Oncol. 2012;29:3381–8.CrossRefPubMed

22.

Petryszak R, Burdett T, Fiorelli B, Fonseca N a., Gonzalez-Porta M, Hastings E, Huber W, Jupp S, Keays M, Kryvych N, McMurry J, Marioni JC, Malone J, Megy K, Rustici G, Tang AY, Taubert J, Williams E, Mannion O, Parkinson HE, Brazma A. Expression Atlas update - a database of gene and transcript expression from microarray- and sequencing-based functional genomics experiments. Nucleic Acids Res. 2014;42(December 2013):926–32.CrossRef

23.

Herron BJ, Rao C, Liu S, Laprade L, Richardson J a., Oliveri E, Semsarian C, Millar SE, Stubbs L, Beier DR. A mutation in NFkB interacting protein 1 results in cardiomyopathy and abnormal skin development in wa3 mice. Hum Mol Genet. 2005;14:667–77.CrossRefPubMed

24.

Elliott G, Hong C, Xing X, Zhou X, Li D, Coarfa C, Bell RJ a., Maire CL, Ligon KL, Sigaroudinia M, Gascard P, Tlsty TD, Harris RA, Schalkwyk LC, Bilenky M, Mill J, Farnham PJ, Kellis M, Marra M a., Milosavljevic A, Hirst M, Stormo GD, Wang T, Costello JF. Intermediate DNA methylation is a conserved signature of genome regulation. Nat Commun. 2015;6:6363.CrossRefPubMedPubMedCentral

25.

Illingworth RS, Gruenewald-Schneider U, Webb S, Kerr ARW, James KD, Turner DJ, Smith C, Harrison DJ, Andrews R, Bird AP. Orphan CpG islands identify numerous conserved promoters in the mammalian genome. PLoS Genet. 2010;6:e1001134.CrossRefPubMedPubMedCentral

26.

Jones P a. Functions of DNA methylation: islands, start sites, gene bodies and beyond. Nat Rev Genet. 2012;13:484–92.CrossRefPubMed

27.

Song Q, Decato B, Hong EE, Zhou M, Fang F, Qu J, et al. A reference methylome database and analysis pipeline to facilitate integrative and comparative epigenomics. PLoS One 2013; 8:e81148.

28.

Court F, Tayama C, Romanelli V, Martin-Trujillo A, Iglesias-Platas I, Okamura K, et al. Genome-wide parent-of-origin DNA methylation analysis reveals the intricacies of human imprinting and suggests a germline methylation-independent mechanism of establishment. Genome Res. 2014; 24:554–69.

29.

Okae H, Chiba H, Hiura H, Hamada H, Sato A. Genome-wide analysis of DNA methylation dynamics during early human development. PLoS Genet. 2014;10:1–12.CrossRef

30.

Gimelbrant A, Hutchinson JN, Thompson BR, Chess A. Widespread monoallelic expression on human autosomes. Science. 2007;318:1136–40.CrossRefPubMed

31.

Kerkel K, Spadola A, Yuan E, Kosek J, Jiang L, Hod E, Li K, Murty V V, Schupf N, Vilain E, Morris M, Haghighi F, Tycko B. Genomic surveys by methylation-sensitive SNP analysis identify sequence-dependent allele-specific DNA methylation. Nat Genet. 2008;40:904–8.CrossRefPubMed

32.

Schalkwyk LC, Meaburn EL, Smith R, Dempster EL, Jeffries AR, Davies MN, Plomin R, Mill J. Allelic skewing of DNA methylation is widespread across the genome. Am J Hum Genet. 2010;86:196–212.CrossRefPubMedPubMedCentral

33.

Zhang Y, Rohde C, Reinhardt R, Voelcker-Rehage C, Jeltsch A. Non-imprinted allele-specific DNA methylation on human autosomes. Genome Biol. 2009;10:R138.CrossRefPubMedPubMedCentral

34.

Kacem S, Feil R. Chromatin mechanisms in genomic imprinting. Mamm Genome. 2009;20:544–56.CrossRefPubMed

35.

Choufani S, Shapiro JS, Susiarjo M, Butcher DT, Grafodatskaya D, Lou Y, Ferreira JC, Pinto D, Scherer SW, Shaffer LG, Coullin P, Caniggia I, Beyene J, Slim R, Bartolomei MS, Weksberg R. A novel approach identifies new differentially methylated regions (DMRs) associated with imprinted genes. Genome Res. 2011;21:465–76.CrossRefPubMedPubMedCentral

36.

Metsalu T, Viltrop T, Tiirats A, Rajashekar B, Reimann E, Kõks S, Rull K, Milani L, Acharya G, Basnet P, Vilo J, Mägi R, Metspalu A, Peters M, Haller-Kikkatalo K, Salumets A. Using RNA sequencing for identifying gene imprinting and random monoallelic expression in human placenta. Epigenetics. 2014;9:1397–409.CrossRefPubMedPubMedCentral

37.

Stelzer Y, Ronen D, Bock C, Boyle P, Meissner A, Benvenisty N. Identification of novel imprinted differentially methylated regions by global analysis of human-parthenogenetic-induced pluripotent stem cells. Stem Cell Rep. 2013;1:79–89.CrossRef

38.

Barbaux S, Gascoin-Lachambre G, Buffat C, Monnier P, Mondon F, Tonanny MB, Pinard A, Auer J, Bessières B, Barlier A, Jacques S, Simeoni U, Dandolo L, Letourneur F, Jammes H, Vaiman D. A genome-wide approach reveals novel imprinted genes expressed in the human placenta. Epigenetics. 2012;7(February 2015):1079–90.CrossRefPubMedPubMedCentral

39.

Yuen RK, Jiang R, Peñaherrera MS, McFadden DE, Robinson WP. Genome-wide mapping of imprinted differentially methylated regions by DNA methylation profiling of human placentas from triploidies. Epigenetics Chromatin. 2011;4:10.CrossRefPubMedPubMedCentral

40.

Baran Y, Subramaniam M, Biton A, Tukiainen T, Tsang EK, Rivas MA, et al. The landscape of genomic imprinting across diverse adult human tissues. Genome Res. 2015;25:927–36.

41.

Beygo J, Ammerpohl O, Gritzan D, Heitmann M, Rademacher K, Richter J, Caliebe A, Siebert R, Horsthemke B, Buiting K. Deep bisulfite sequencing of aberrantly methylated Loci in a patient with multiple methylation defects. PLoS One. 2013;8:e76953.CrossRefPubMedPubMedCentral

42.

Caliebe A, Richter J, Ammerpohl O, Kanber D, Beygo J, Bens S, Haake A, Jüttner E, Korn B, Mackay DJG, Martin-Subero JI, Nagel I, Sebire NJ, Seidmann L, Vater I, von Kaisenberg CS, Temple IK, Horsthemke B, Buiting K, Siebert R. A familial disorder of altered DNA-methylation. J Med Genet. 2014;51:407–12.CrossRefPubMed

Title: Genome-wide DNA methylation analysis of transient neonatal diabetes type 1 patients with mutations in ZFP57
Authors: Mads Bak
Susanne E. Boonen
Christina Dahl
Johanne M. D. Hahnemann
Deborah J. D. G. Mackay
Zeynep Tümer
Karen Grønskov
I. Karen Temple
Per Guldberg
Niels Tommerup
Publication date: 01-12-2016
Publisher: BioMed Central
Published in: BMC Medical Genetics / Issue 1/2016
Electronic ISSN: 1471-2350
DOI: https://doi.org/10.1186/s12881-016-0292-4

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Springer Medicine

Genome-wide DNA methylation analysis of transient neonatal diabetes type 1 patients with mutations in ZFP57

Abstract

Background

Methods

Results

Conclusions

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

Background

Methods

Results

Conclusions

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