Long-read single-molecule maps of the functional methylome

Hila Sharim; Assaf Grunwald; Tslil Gabrieli; Yael Michaeli; Sapir Margalit; Dmitry Torchinsky; Rani Arielly; Gil Nifker; Matyas Juhasz; Felix Gularek; Miguel Almalvez; Brandon Dufault; Sreetama Sen Chandra; Alexander Liu; Surajit Bhattacharya; Yi Wen Chen; Eric Vilain; Kathryn R. Wagner; Jonathan Pevsner; Jeff Reifenberger; Ernest T. Lam; Alex R. Hastie; Han Cao; Hayk Barseghyan; Elmar Weinhold; Yuval Ebenstein

doi:10.1101/gr.240739.118

Long-read single-molecule maps of the functional methylome

Hila Sharim, Assaf Grunwald, Tslil Gabrieli, Yael Michaeli, Sapir Margalit, Dmitry Torchinsky, Rani Arielly, Gil Nifker, Matyas Juhasz, Felix Gularek, Miguel Almalvez, Brandon Dufault, Sreetama Sen Chandra, Alexander Liu, Surajit Bhattacharya, Yi Wen Chen, Eric Vilain, Kathryn R. Wagner, Jonathan Pevsner, Jeff ReifenbergerErnest T. Lam, Alex R. Hastie, Han Cao, Hayk Barseghyan, Elmar Weinhold, Yuval Ebenstein

Kennedy Krieger Institute

Research output: Contribution to journal › Article › peer-review

12 Scopus citations

Abstract

We report on the development of a methylation analysis workflow for optical detection of fluorescent methylation profiles along chromosomal DNA molecules. In combination with Bionano Genomics genome mapping technology, these profiles provide a hybrid genetic/epigenetic genome-wide map composed of DNA molecules spanning hundreds of kilobase pairs. The method provides kilobase pair–scale genomic methylation patterns comparable to whole-genome bisulfite sequencing (WGBS) along genes and regulatory elements. These long single-molecule reads allow for methylation variation calling and analysis of large structural aberrations such as pathogenic macrosatellite arrays not accessible to single-cell second-generation sequencing. The method is applied here to study facioscapulohumeral muscular dystrophy (FSHD), simultaneously recording the haplotype, copy number, and methylation status of the disease-associated, highly repetitive locus on Chromosome 4q.

Original language	English (US)
Pages (from-to)	646-656
Number of pages	11
Journal	Genome research
Volume	29
Issue number	4
DOIs	https://doi.org/10.1101/gr.240739.118
State	Published - Apr 2019

ASJC Scopus subject areas

Genetics
Genetics(clinical)

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10.1101/gr.240739.118

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Sharim, H., Grunwald, A., Gabrieli, T., Michaeli, Y., Margalit, S., Torchinsky, D., Arielly, R., Nifker, G., Juhasz, M., Gularek, F., Almalvez, M., Dufault, B., Chandra, S. S., Liu, A., Bhattacharya, S., Chen, Y. W., Vilain, E., Wagner, K. R., Pevsner, J., ... Ebenstein, Y. (2019). Long-read single-molecule maps of the functional methylome. Genome research, 29(4), 646-656. https://doi.org/10.1101/gr.240739.118

Sharim, H, Grunwald, A, Gabrieli, T, Michaeli, Y, Margalit, S, Torchinsky, D, Arielly, R, Nifker, G, Juhasz, M, Gularek, F, Almalvez, M, Dufault, B, Chandra, SS, Liu, A, Bhattacharya, S, Chen, YW, Vilain, E, Wagner, KR, Pevsner, J, Reifenberger, J, Lam, ET, Hastie, AR, Cao, H, Barseghyan, H, Weinhold, E & Ebenstein, Y 2019, 'Long-read single-molecule maps of the functional methylome', Genome research, vol. 29, no. 4, pp. 646-656. https://doi.org/10.1101/gr.240739.118

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title = "Long-read single-molecule maps of the functional methylome",

abstract = "We report on the development of a methylation analysis workflow for optical detection of fluorescent methylation profiles along chromosomal DNA molecules. In combination with Bionano Genomics genome mapping technology, these profiles provide a hybrid genetic/epigenetic genome-wide map composed of DNA molecules spanning hundreds of kilobase pairs. The method provides kilobase pair–scale genomic methylation patterns comparable to whole-genome bisulfite sequencing (WGBS) along genes and regulatory elements. These long single-molecule reads allow for methylation variation calling and analysis of large structural aberrations such as pathogenic macrosatellite arrays not accessible to single-cell second-generation sequencing. The method is applied here to study facioscapulohumeral muscular dystrophy (FSHD), simultaneously recording the haplotype, copy number, and methylation status of the disease-associated, highly repetitive locus on Chromosome 4q.",

author = "Hila Sharim and Assaf Grunwald and Tslil Gabrieli and Yael Michaeli and Sapir Margalit and Dmitry Torchinsky and Rani Arielly and Gil Nifker and Matyas Juhasz and Felix Gularek and Miguel Almalvez and Brandon Dufault and Chandra, {Sreetama Sen} and Alexander Liu and Surajit Bhattacharya and Chen, {Yi Wen} and Eric Vilain and Wagner, {Kathryn R.} and Jonathan Pevsner and Jeff Reifenberger and Lam, {Ernest T.} and Hastie, {Alex R.} and Han Cao and Hayk Barseghyan and Elmar Weinhold and Yuval Ebenstein",

note = "Funding Information: We thank Professor D. Gabellini for his kind gift of the CH16-291A23 BAC and K. Glensk for preparing M.TaqI as well as for analyzing M.TaqI labeling efficiency at different CpG methylation levels. This study was funded by the German–Israeli Foundation for Scientific Research and Development (I-1196-195.9/2012; E.W. and Y.E.), the BeyondSeq consortium (Horizon 2020 EC program 634890; Y.E.), the European Research Councils starter grant (337830; Y.E.), the i-Core program of the Israel Science Foundation (1902/12; Y.E.), the National Institutes of Health (NIH) U54HD060848 (K.R.W.), and NIH U01MH106884 (J.P.). Publisher Copyright: {\textcopyright} 2019 Sharim et al.",

year = "2019",

month = apr,

doi = "10.1101/gr.240739.118",

language = "English (US)",

volume = "29",

pages = "646--656",

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AU - Sharim, Hila

AU - Grunwald, Assaf

AU - Gabrieli, Tslil

AU - Michaeli, Yael

AU - Margalit, Sapir

AU - Torchinsky, Dmitry

AU - Arielly, Rani

AU - Nifker, Gil

AU - Juhasz, Matyas

AU - Gularek, Felix

AU - Almalvez, Miguel

AU - Dufault, Brandon

AU - Chandra, Sreetama Sen

AU - Liu, Alexander

AU - Bhattacharya, Surajit

AU - Chen, Yi Wen

AU - Vilain, Eric

AU - Wagner, Kathryn R.

AU - Pevsner, Jonathan

AU - Reifenberger, Jeff

AU - Lam, Ernest T.

AU - Hastie, Alex R.

AU - Cao, Han

AU - Barseghyan, Hayk

AU - Weinhold, Elmar

AU - Ebenstein, Yuval

N1 - Funding Information: We thank Professor D. Gabellini for his kind gift of the CH16-291A23 BAC and K. Glensk for preparing M.TaqI as well as for analyzing M.TaqI labeling efficiency at different CpG methylation levels. This study was funded by the German–Israeli Foundation for Scientific Research and Development (I-1196-195.9/2012; E.W. and Y.E.), the BeyondSeq consortium (Horizon 2020 EC program 634890; Y.E.), the European Research Councils starter grant (337830; Y.E.), the i-Core program of the Israel Science Foundation (1902/12; Y.E.), the National Institutes of Health (NIH) U54HD060848 (K.R.W.), and NIH U01MH106884 (J.P.). Publisher Copyright: © 2019 Sharim et al.

PY - 2019/4

Y1 - 2019/4

N2 - We report on the development of a methylation analysis workflow for optical detection of fluorescent methylation profiles along chromosomal DNA molecules. In combination with Bionano Genomics genome mapping technology, these profiles provide a hybrid genetic/epigenetic genome-wide map composed of DNA molecules spanning hundreds of kilobase pairs. The method provides kilobase pair–scale genomic methylation patterns comparable to whole-genome bisulfite sequencing (WGBS) along genes and regulatory elements. These long single-molecule reads allow for methylation variation calling and analysis of large structural aberrations such as pathogenic macrosatellite arrays not accessible to single-cell second-generation sequencing. The method is applied here to study facioscapulohumeral muscular dystrophy (FSHD), simultaneously recording the haplotype, copy number, and methylation status of the disease-associated, highly repetitive locus on Chromosome 4q.

AB - We report on the development of a methylation analysis workflow for optical detection of fluorescent methylation profiles along chromosomal DNA molecules. In combination with Bionano Genomics genome mapping technology, these profiles provide a hybrid genetic/epigenetic genome-wide map composed of DNA molecules spanning hundreds of kilobase pairs. The method provides kilobase pair–scale genomic methylation patterns comparable to whole-genome bisulfite sequencing (WGBS) along genes and regulatory elements. These long single-molecule reads allow for methylation variation calling and analysis of large structural aberrations such as pathogenic macrosatellite arrays not accessible to single-cell second-generation sequencing. The method is applied here to study facioscapulohumeral muscular dystrophy (FSHD), simultaneously recording the haplotype, copy number, and methylation status of the disease-associated, highly repetitive locus on Chromosome 4q.

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JF - Genome research

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Long-read single-molecule maps of the functional methylome

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