The DOI matches its Crossref record; 9 of the 9 references it cites were found in a registry or an index.
Dynamic changes in the human methylome during differentiation
Open accessAbstract
DNA methylation is a critical epigenetic regulator in mammalian development. Here, we present a whole-genome comparative view of DNA methylation using bisulfite sequencing of three cultured cell types representing progressive stages of differentiation: human embryonic stem cells (hESCs), a fibroblastic differentiated derivative of the hESCs, and neonatal fibroblasts. As a reference, we compared our maps with a methylome map of a fully differentiated adult cell type, mature peripheral blood mononuclear cells (monocytes). We observed many notable common and cell-type-specific features among all cell types. Promoter hypomethylation (both CG and CA) and higher levels of gene body methylation were positively correlated with transcription in all cell types. Exons were more highly methylated than introns, and sharp transitions of methylation occurred at exon–intron boundaries, suggesting a role for differential methylation in transcript splicing. Developmental stage was reflected in both the level of global methylation and extent of non-CpG methylation, with hESC highest, fibroblasts intermediate, and monocytes lowest. Differentiation-associated differential methylation profiles were observed for developmentally regulated genes, including the HOX clusters, other homeobox transcription factors, and pluripotence-associated genes such as POU5F1 , TCF3 , and KLF4 . Our results highlight the value of high-resolution methylation maps, in conjunction with other systems-level analyses, for investigation of previously undetectable developmental regulatory mechanisms.
Overview
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Verification
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Citations
Cites
A bivalent chromatin structure marks key developmental genes in embryonic stem cells
Bernstein, B. E., Mikkelsen, T. S., Xie, X., Kamal, M., Huebert, D. J., Cuff, J., Fry, B., Meissner, A., Wernig, M., Plath, K., et al. (2006) · Cell · doi:10.1016/j.cell.2006.02.041 · Cited by 5,361
Genome-wide maps of chromatin state in pluripotent and lineage-committed cells
Mikkelsen, T. S., Ku, M., Jaffe, D. B., Issac, B., Lieberman, E., Giannoukos, G., Alvarez, P., Brockman, W., Kim, T.-K., Koche, R. P., et al. (2007) · Nature · doi:10.1038/nature06008 · Cited by 4,129
Epigenetic Reprogramming in Mammalian Development
Reik, W., Dean, W., & Walter, J. (2001) · Science · doi:10.1126/science.1063443 · Cited by 3,078
Genome-scale DNA methylation maps of pluripotent and differentiated cells
Meissner, A., Mikkelsen, T. S., Gu, H., Wernig, M., Hanna, J., Sivachenko, A., Zhang, X., Bernstein, B. E., Nusbaum, C., Jaffe, D. B., et al. (2008) · Nature · doi:10.1038/nature07107 · Cited by 2,536
Transcription of IAP endogenous retroviruses is constrained by cytosine methylation
Walsh, C. P., Chaillet, J. R., & Bestor, T. H. (1998) · Nature Genetics · doi:10.1038/2413 · Cited by 1,105
The diploid genome sequence of an Asian individual
Wang, J., Wang, W., Li, R., Li, Y., Tian, G., Goodman, L., Fan, W., Zhang, J., Li, J., Zhang, J., et al. (2008) · Nature · doi:10.1038/nature07484 · Cited by 924
Self-citationChromatin organization marks exon-intron structure
Schwartz, S., Meshorer, E., & Ast, G. (2009) · Nature Structural & Molecular Biology · doi:10.1038/nsmb.1659 · Cited by 638
The human SWI/SNF subunit Brm is a regulator of alternative splicing
Batsché, E., Yaniv, M., & Muchardt, C. (2006) · Nature Structural & Molecular Biology · doi:10.1038/nsmb1030 · Cited by 471
Regulatory networks define phenotypic classes of human stem cell lines
Müller, F.-J., Laurent, L. C., Kostka, D., Ulitsky, I., Williams, R., Lu, C., Park, I.-H., Rao, M. S., Shamir, R., Schwartz, P. H., et al. (2008) · Nature · doi:10.1038/nature07213 · Cited by 343
Self-citation
Cited by
Functions of DNA methylation: islands, start sites, gene bodies and beyond
Jones, P. A. (2012) · Nature Reviews Genetics · doi:10.1038/nrg3230 · Cited by 6,061
DNA methylation: roles in mammalian development
Smith, Z. D., & Meissner, A. (2013) · Nature Reviews Genetics · doi:10.1038/nrg3354 · Cited by 3,045
High density DNA methylation array with single CpG site resolution
Bibikova, M., Barnes, B., Tsan, C., Ho, V., Klotzle, B., Le, J. M., Delano, D., Zhang, L., Schroth, G. P., Gunderson, K. L., et al. (2011) · Genomics · doi:10.1016/j.ygeno.2011.07.007 · Cited by 1,727
“Other categories represented were non-CpG sites [9,31], DNase hypersensitive sites [32,33] and differentially methylated regions [18,34].”
BackgroundCharting a dynamic DNA methylation landscape of the human genome
Ziller, M. J., Gu, H., Müller, F., Donaghey, J., Tsai, L. T.-Y., Kohlbacher, O., De Jager, P. L., Rosen, E. D., Bennett, D. A., Bernstein, B. E., et al. (2013) · Nature · doi:10.1038/nature12433 · Cited by 1,357
The Dynamics of Genome-wide DNA Methylation Reprogramming in Mouse Primordial Germ Cells
Seisenberger, S., Andrews, S., Krueger, F., Arand, J., Walter, J., Santos, F., Popp, C., Thienpont, B., Dean, W., & Reik, W. (2012) · Molecular Cell · doi:10.1016/j.molcel.2012.11.001 · Cited by 973
DNA methylation and body-mass index: a genome-wide analysis
Dick, K. J., Nelson, C. P., Tsaprouni, L., Sandling, J. K., Aïssi, D., Wahl, S., Meduri, E., Morange, P.-E., Gagnon, F., Grallert, H., et al. (2014) · The Lancet · doi:10.1016/s0140-6736(13)62674-4 · Cited by 778
The Honey Bee Epigenomes: Differential Methylation of Brain DNA in Queens and Workers
Lyko, F., Foret, S., Kucharski, R., Wolf, S., Falckenhayn, C., & Maleszka, R. (2010) · PLoS Biology · doi:10.1371/journal.pbio.1000506 · Cited by 727
Distribution, recognition and regulation of non-CpG methylation in the adult mammalian brain
Guo, J. U., Su, Y., Shin, J. H., Shin, J., Li, H., Xie, B., Zhong, C., Hu, S., Le, T., Fan, G., et al. (2014) · Nature Neuroscience · doi:10.1038/nn.3607 · Cited by 714
Neuronal activity modifies the DNA methylation landscape in the adult brain
Guo, J. U., Ma, D. K., Mo, H., Ball, M. P., Jang, M.-H., Bonaguidi, M. A., Balazer, J. A., Eaves, H. L., Xie, B., Ford, E., et al. (2011) · Nature Neuroscience · doi:10.1038/nn.2900 · Cited by 669
Evaluation of the Infinium Methylation 450K technology
Dedeurwaerder, S., Defrance, M., Calonne, E., Denis, H., Sotiriou, C., & Fuks, F. (2011) · Epigenomics · doi:10.2217/epi.11.105 · Cited by 569
DNA methylation dynamics in health and disease
Bergman, Y., & Cedar, H. (2013) · Nature Structural & Molecular Biology · doi:10.1038/nsmb.2518 · Cited by 592
CpG and non-CpG methylation in epigenetic gene regulation and brain function
Jang, H., Shin, W., Lee, J., & Do, J. (2017) · Genes · doi:10.3390/genes8060148 · Cited by 427
Dynamic integration of splicing within gene regulatory pathways
Braunschweig, U., Gueroussov, S., Plocik, A. M., Graveley, B. R., & Blencowe, B. J. (2013) · Cell · doi:10.1016/j.cell.2013.02.034 · Cited by 406
Grundberg, E., Meduri, E., Sandling, J. K., Hedman, Å. K., Keildson, S., Buil, A., Busche, S., Yuan, W., Nisbet, J., Sekowska, M., et al. (2013) · The American Journal of Human Genetics · doi:10.1016/j.ajhg.2013.10.004 · Cited by 370
Towards a comprehensive catalogue of validated and target-linked human enhancers
Gasperini, M., Tome, J. M., & Shendure, J. (2020) · Nature Reviews Genetics · doi:10.1038/s41576-019-0209-0 · Cited by 396
Profiling genome-wide DNA methylation
Yong, W.-S., Hsu, F.-M., & Chen, P.-Y. (2016) · Epigenetics & Chromatin · doi:10.1186/s13072-016-0075-3 · Cited by 374
Structural insight into autoinhibition and histone H3-induced activation of DNMT3A
Guo, X., Wang, L., Li, J., Ding, Z., Xiao, J., Yin, X., He, S., Shi, P., Dong, L., Li, G., et al. (2015) · Nature · doi:10.1038/nature13899 · Cited by 361
Self-citationSimultaneous profiling of transcriptome and DNA methylome from a single cell
Hu, Y., Huang, K., An, Q., Du, G., Hu, G., Xue, J., Zhu, X., Wang, C.-Y., Xue, Z., & Fan, G. (2016) · Genome Biology · doi:10.1186/s13059-016-0950-z · Cited by 300
Transcriptional and epigenomic landscapes of CNS and non-CNS vascular endothelial cells
Sabbagh, M. F., Heng, J. S., Luo, C., Castanon, R. G., Nery, J. R., Rattner, A., Goff, L. A., Ecker, J. R., & Nathans, J. (2018) · eLife · doi:10.7554/elife.36187 · Cited by 245
Reddington, J. P., Perricone, S. M., Nestor, C. E., Reichmann, J., Youngson, N. A., Suzuki, M., Reinhardt, D., Dunican, D. S., Prendergast, J. G., Mjoseng, H., et al. (2013) · Genome Biology · doi:10.1186/gb-2013-14-3-r25 · Cited by 240
Interaction with Suv39H1 is critical for Snail-mediated E-cadherin repression in breast cancer
Dong, C., Wu, Y., Wang, Y., Wang, C., Kang, T., Rychahou, P. G., Chi, Y.-I., Evers, B. M., & Zhou, B. P. (2013) · Oncogene · doi:10.1038/onc.2012.169 · Cited by 214
Alternative splicing: decoding an expansive regulatory layer
Irimia, M., & Blencowe, B. J. (2012) · Current Opinion in Cell Biology · doi:10.1016/j.ceb.2012.03.005 · Cited by 177
Hong, E. E., Okitsu, C. Y., Smith, A. D., & Hsieh, C.-L. (2013) · Molecular and Cellular Biology · doi:10.1128/mcb.00220-13 · Cited by 175
Genome-wide nucleosome map and cytosine methylation levels of an ancient human genome
Pedersen, J. S., Valen, E., Velazquez, A. M. V., Parker, B. J., Rasmussen, M., Lindgreen, S., Lilje, B., Tobin, D. J., Kelly, T. K., Vang, S., et al. (2014) · Genome Research · doi:10.1101/gr.163592.113 · Cited by 170
TET proteins regulate the lineage specification and TCR-mediated expansion of iNKT cells
Tsagaratou, A., González-Avalos, E., Rautio, S., Scott-Browne, J. P., Togher, S., Pastor, W. A., Rothenberg, E. V., Chavez, L., Lähdesmäki, H., & Rao, A. (2017) · Nature Immunology · doi:10.1038/ni.3630 · Cited by 154
The role of methylation of DNA in environmental adaptation
Flores, K. B., Wolschin, F., & Amdam, G. V. (2013) · Integrative and Comparative Biology · doi:10.1093/icb/ict019 · Cited by 143
Characterizing the genetic basis of methylome diversity in histologically normal human lung tissue
Shi, J., Marconett, C. N., Duan, J., Hyland, P. L., Li, P., Wang, Z., Wheeler, W., Zhou, B., Campan, M., Lee, D. S., et al. (2014) · Nature Communications · doi:10.1038/ncomms4365 · Cited by 137
Hogart, A., Lichtenberg, J., Ajay, S. S., Anderson, S., NIH Intramural Sequencing Center, Margulies, E. H., & Bodine, D. M. (2012) · Genome Research · doi:10.1101/gr.132878.111 · Cited by 101
Global DNA Hypermethylation in Down Syndrome Placenta
Jin, S., Lee, Y. K., Lim, Y. C., Zheng, Z., Lin, X. M., Ng, D. P. Y., Holbrook, J. D., Law, H. Y., Kwek, K. Y. C., Yeo, G. S. H., et al. (2013) · PLoS Genetics · doi:10.1371/journal.pgen.1003515 · Cited by 99
Mechanistic Basis for Maintenance of CHG DNA Methylation in Plants
Fang, J., Jiang, J., Leichter, S. M., Liu, J., Biswal, M., Khudaverdyan, N., Zhong, X., & Song, J. (2022) · Nature Communications · doi:10.1038/s41467-022-31627-3 · Cited by 69
Sandoval, J. E., Huang, Y.-H., Muise, A., Goodell, M. A., & Reich, N. O. (2019) · Journal of Biological Chemistry · doi:10.1074/jbc.ra118.006795 · Cited by 66
Roost, M. S., Slieker, R. C., Bialecka, M., van Iperen, L., Gomes Fernandes, M. M., He, N., Suchiman, H. E. D., Szuhai, K., Carlotti, F., de Koning, E. J. P., et al. (2017) · Nature Communications · doi:10.1038/s41467-017-01077-3 · Cited by 65
Methylation-Based Therapies for Colorectal Cancer
Cervena, K., Siskova, A., Buchler, T., Vodicka, P., & Vymetalkova, V. (2020) · Cells · doi:10.3390/cells9061540 · Cited by 57
DNA methylation in epigenetic inheritance of metabolic diseases through the male germ line
Illum, L. R. H., Bak, S. T., Lund, S., & Nielsen, A. L. (2018) · Journal of Molecular Endocrinology · doi:10.1530/jme-17-0189 · Cited by 51
Epigenetic reprogramming in mice and humans: From fertilization to primordial germ cell development
Singh, A., Rappolee, D. A., & Ruden, D. M. (2023) · Cells · doi:10.3390/cells12141874 · Cited by 50
Fine-tuning of gene expression through the Mettl3-Mettl14-Dnmt1 axis controls ESC differentiation
Quarto, G., Li Greci, A., Bizet, M., Penning, A., Primac, I., Murisier, F., Garcia-Martinez, L., Borges, R. L., Gao, Q., Cingaram, P. K. R., et al. (2025) · Cell · doi:10.1016/j.cell.2024.12.009 · Cited by 50
Yu, D.-H., Ware, C., Waterland, R. A., Zhang, J., Chen, M.-H., Gadkari, M., Kunde-Ramamoorthy, G., Nosavanh, L. M., & Shen, L. (2013) · Molecular and Cellular Biology · doi:10.1128/mcb.01124-12 · Cited by 48
Multi-omics integration strategies for animal epigenetic studies — A review
Kim, D.-Y., & Kim, J.-M. (2021) · Animal Bioscience · doi:10.5713/ab.21.0042 · Cited by 47
Li-Tempel, T., Larra, M. F., Sandt, E., Mériaux, S. B., Schote, A. B., Schächinger, H., Muller, C. P., & Turner, J. D. (2016) · Clinical Epigenetics · doi:10.1186/s13148-016-0180-y · Cited by 46
Sarda, S., Das, A., Vinson, C., & Hannenhalli, S. (2017) · Genome Research · doi:10.1101/gr.212050.116 · Cited by 43
A concise review of human brain methylome during aging and neurodegenerative diseases
Prasad G, R., & Jho, E.-H. (2019) · BMB Reports · doi:10.5483/bmbrep.2019.52.10.215 · Cited by 31
Martino, D., & Saffery, R. (2015) · doi:10.1101/032862 · Cited by 22
Significant association between DRD3 gene body methylation and schizophrenia
Dai, D., Cheng, J., Zhou, K., Lv, Y., Zhuang, Q., Zheng, R., Zhang, K., Jiang, D., Gao, S., & Duan, S. (2014) · Psychiatry Research · doi:10.1016/j.psychres.2014.08.032 · Cited by 21
Zhang, Z., Liu, J., Kaur, M., & Krantz, I. D. (2012) · Genomics · doi:10.1016/j.ygeno.2012.01.002 · Cited by 18
Metadata
- Authors
- Laurent, L., Wong, E., Li, G., Huynh, T., Tsirigos, A., Ong, C. T., Low, H. M., Kin Sung, K. W., Rigoutsos, I., Loring, J., & Wei, C.-L.
- Venue
- Genome Research
- Publisher
- Cold Spring Harbor Laboratory
- Published
- 2010-02-04
- Volume
- 20
- Issue
- 3
- Pages
- 320-331
- ISSN
- 1088-9051 (ISSN-L)
- OpenAlex
- W1986849101
- Cited by
- 1,041
- References
- 9
- Type
- posted content
- Language
- en
- Open access
- hybrid
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
Data sources
Bibliographic data: Semantic Scholar, OpenAlex, Crossref.
Contains information from the Semantic Scholar Academic Graph Datasets, made available under the ODC Attribution License (ODC-BY 1.0).
Semantic Scholar’s data is described in: Kinney, R., et al. (2023). The Semantic Scholar Open Data Platform. arXiv:2301.10140.
