The DOI matches its Crossref record; 21 of the 21 references it cites were found in a registry or an index.
Epigenomic Analysis of Multilineage Differentiation of Human Embryonic Stem Cells
Open accessAbstract
SUMMARY Epigenetic mechanisms have been proposed to play crucial roles in mammalian development, but their precise functions are only partially understood. To investigate epigenetic regulation of embryonic development, we differentiated human embryonic stem cells into mesendoderm, neural progenitor cells, trophoblast-like cells, and mesenchymal stem cells, and systematically characterized DNA methylation, chromatin modifications, and the transcriptome in each lineage. We found that promoters that are active in early developmental stages tend to be CG rich and mainly engage H3K27me3 upon silencing in non-expressing lineages. By contrast, promoters for genes expressed preferentially at later stages are often CG poor and primarily employ DNA methylation upon repression. Interestingly, the early developmental regulatory genes are often located in large genomic domains that are generally devoid of DNA methylation in most lineages, which we termed DNA methylation valleys (DMVs). Our results suggest that distinct epigenetic mechanisms regulate early and late stages of ES cell differentiation.
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
Gapped BLAST and PSI-BLAST: a new generation of protein database search programs
Altschul, S. (1997) · Nucleic Acids Research · doi:10.1093/nar/25.17.3389 · Cited by 73,302
Chromatin modifications and their function
Kouzarides, T. (2007) · Cell · doi:10.1016/j.cell.2007.02.005 · Cited by 10,883 · cited 2×
“Enzymes responsible for methylation of histone H3 at lysine 4, 9, and 27, in particular, are essential for embryogenesis (Kouzarides, 2007; Vastenhouw and Schier, 2012).”
DNA methylation patterns and epigenetic memory
Bird, A. (2002) · Genes & Development · doi:10.1101/gad.947102 · Cited by 7,124
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
Human DNA methylomes at base resolution show widespread epigenomic differences
Lister, R., Pelizzola, M., Dowen, R. H., Hawkins, R. D., Hon, G., Tonti-Filippini, J., Nery, J. R., Lee, L., Ye, Z., Ngo, Q.-M., et al. (2009) · Nature · doi:10.1038/nature08514 · Cited by 4,673
Self-citationGREAT improves functional interpretation of cis-regulatory regions
McLean, C. Y., Bristor, D., Hiller, M., Clarke, S. L., Schaar, B. T., Lowe, C. B., Wenger, A. M., & Bejerano, G. (2010) · Nature Biotechnology · doi:10.1038/nbt.1630 · Cited by 4,502
Targeted mutation of the DNA methyltransferase gene results in embryonic lethality
Li, E., Bestor, T. H., & Jaenisch, R. (1992) · Cell · doi:10.1016/0092-8674(92)90611-f · Cited by 3,984
Highly efficient neural conversion of human ES and iPS cells by dual inhibition of SMAD signaling
Chambers, S. M., Fasano, C. A., Papapetrou, E. P., Tomishima, M., Sadelain, M., & Studer, L. (2009) · Nature Biotechnology · doi:10.1038/nbt.1529 · Cited by 3,620
Mapping and analysis of chromatin state dynamics in nine human cell types
Ernst, J., Kheradpour, P., Mikkelsen, T. S., Shoresh, N., Ward, L. D., Epstein, C. B., Zhang, X., Wang, L., Issner, R., Coyne, M., et al. (2011) · Nature · doi:10.1038/nature09906 · Cited by 2,898
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
Cited by
Integrative analysis of 111 reference human epigenomes
Roadmap Epigenomics Consortium, Kundaje, A., Meuleman, W., Ernst, J., Bilenky, M., Yen, A., Heravi-Moussavi, A., Kheradpour, P., Zhang, Z., Wang, J., et al. (2015) · Nature · doi:10.1038/nature14248 · Cited by 6,368
“Extended data (1-12), supplementary figures (S1-S13), supplementary tables (S1-S6) are available in the online version of the paper.”
BackgroundSelf-citationFunction and information content of DNA methylation
Schübeler, D. (2015) · Nature · doi:10.1038/nature14192 · Cited by 2,060
Chromatin architecture reorganization during stem cell differentiation
Dixon, J. R., Jung, I., Selvaraj, S., Shen, Y., Antosiewicz-Bourget, J. E., Lee, A. Y., Ye, Z., Kim, A., Rajagopal, N., Xie, W., et al. (2015) · Nature · doi:10.1038/nature14222 · Cited by 1,646
Self-citationA comparative encyclopedia of DNA elements in the mouse genome
Yue, F., Cheng, Y., Breschi, A., Vierstra, J., Wu, W., Ryba, T., Sandstrom, R., Ma, Z., Davis, C., Pope, B. D., et al. (2014) · Nature · doi:10.1038/nature13992 · Cited by 1,781
Self-citationGene Body Methylation Can Alter Gene Expression and Is a Therapeutic Target in Cancer
Yang, X., Han, H., De Carvalho, D. D., Lay, F. D., Jones, P. A., & Liang, G. (2014) · Cancer Cell · doi:10.1016/j.ccr.2014.07.028 · Cited by 1,199
Epigenomic Signatures of Neuronal Diversity in the Mammalian Brain
Mo, A., Mukamel, E. A., Davis, F. P., Luo, C., Henry, G. L., Picard, S., Urich, M. A., Nery, J. R., Sejnowski, T. J., Lister, R., et al. (2015) · Neuron · doi:10.1016/j.neuron.2015.05.018 · Cited by 739
Self-citationSun, D., Luo, M., Jeong, M., Rodriguez, B., Xia, Z., Hannah, R., Wang, H., Le, T., Faull, K. F., Chen, R., et al. (2014) · Cell Stem Cell · doi:10.1016/j.stem.2014.03.002 · Cited by 686
Human body epigenome maps reveal noncanonical DNA methylation variation
Schultz, M. D., He, Y., Whitaker, J. W., Hariharan, M., Mukamel, E. A., Leung, D., Rajagopal, N., Nery, J. R., Urich, M. A., Chen, H., et al. (2015) · Nature · doi:10.1038/nature14465 · Cited by 690
Self-citationChromatin modifiers and remodellers: regulators of cellular differentiation
Chen, T., & Dent, S. Y. R. (2014) · Nature Reviews Genetics · doi:10.1038/nrg3607 · Cited by 619
Chu, L.-F., Leng, N., Zhang, J., Hou, Z., Mamott, D., Vereide, D. T., Choi, J., Kendziorski, C., Stewart, R., & Thomson, J. A. (2016) · Genome Biology · doi:10.1186/s13059-016-1033-x · Cited by 477
“To begin investigating lineage-specific transcriptomic features at single-cell resolution, we performed a cohort of scRNA-seq experiments profiling snapshots of lineagespecific progenitor cells differentiated from H1 human ES cells using our established differentiation protocols, all adapted to chemically-defined cult…”
MethodSelf-citationDeans, C., & Maggert, K. A. (2015) · Genetics · doi:10.1534/genetics.114.173492 · Cited by 554
Rivera, C. M., & Ren, B. (2013) · Cell · doi:10.1016/j.cell.2013.09.011 · Cited by 550
Self-citationH3K4me3 breadth is linked to cell identity and transcriptional consistency
Benayoun, B. A., Pollina, E. A., Ucar, D., Mahmoudi, S., Karra, K., Wong, E. D., Devarajan, K., Daugherty, A. C., Kundaje, A. B., Mancini, E., et al. (2014) · Cell · doi:10.1016/j.cell.2014.06.027 · Cited by 536
HiCRep: assessing the reproducibility of Hi-C data using a stratum-adjusted correlation coefficient
Yang, T., Zhang, F., Yardımcı, G. G., Song, F., Hardison, R. C., Noble, W. S., Yue, F., & Li, Q. (2017) · Genome Research · doi:10.1101/gr.220640.117 · Cited by 533
Transcriptional and Epigenetic Dynamics during Specification of Human Embryonic Stem Cells
Gifford, C. A., Ziller, M. J., Gu, H., Trapnell, C., Donaghey, J., Tsankov, A., Shalek, A. K., Kelley, D. R., Shishkin, A. A., Issner, R., et al. (2013) · Cell · doi:10.1016/j.cell.2013.04.037 · Cited by 435
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
A transcriptomic and epigenomic cell atlas of the mouse primary motor cortex
Yao, Z., Liu, H., Xie, F., Fischer, S., Adkins, R. S., Aldridge, A. I., Ament, S. A., Bartlett, A., Behrens, M. M., Van den Berge, K., et al. (2021) · Nature · doi:10.1038/s41586-021-03500-8 · Cited by 398
Self-citationCerebral Organoids Recapitulate Epigenomic Signatures of the Human Fetal Brain
Luo, C., Lancaster, M. A., Castanon, R., Nery, J. R., Knoblich, J. A., & Ecker, J. R. (2016) · Cell Reports · doi:10.1016/j.celrep.2016.12.001 · Cited by 370
Self-citationChen, K., Chen, Z., Wu, D., Zhang, L., Lin, X., Su, J., Rodriguez, B., Xi, Y., Xia, Z., Chen, X., et al. (2015) · Nature Genetics · doi:10.1038/ng.3385 · Cited by 373
Dnmt3a and Dnmt3b have overlapping and distinct functions in hematopoietic stem cells
Challen, G. A., Sun, D., Mayle, A., Jeong, M., Luo, M., Rodriguez, B., Mallaney, C., Celik, H., Yang, L., Xia, Z., et al. (2014) · Cell Stem Cell · doi:10.1016/j.stem.2014.06.018 · Cited by 354
Loss of Tet Enzymes Compromises Proper Differentiation of Embryonic Stem Cells
Dawlaty, M. M., Breiling, A., Le, T., Barrasa, M. I., Raddatz, G., Gao, Q., Powell, B. E., Cheng, A. W., Faull, K. F., Lyko, F., et al. (2014) · Developmental Cell · doi:10.1016/j.devcel.2014.03.003 · Cited by 338
Large conserved domains of low DNA methylation maintained by Dnmt3a
Jeong, M., Sun, D., Luo, M., Huang, Y., Challen, G. A., Rodriguez, B., Zhang, X., Chavez, L., Wang, H., Hannah, R., et al. (2014) · Nature Genetics · doi:10.1038/ng.2836 · Cited by 324
CRISPR/Cas9-based engineering of the epigenome
Pulecio, J., Verma, N., Mejía-Ramírez, E., Huangfu, D., & Raya, A. (2017) · Cell Stem Cell · doi:10.1016/j.stem.2017.09.006 · Cited by 300
Methods for ChIP-seq analysis: A practical workflow and advanced applications
Nakato, R., & Sakata, T. (2021) · Methods · doi:10.1016/j.ymeth.2020.03.005 · Cited by 267
A statistical approach for identifying differential distributions in single-cell RNA-seq experiments
Korthauer, K. D., Chu, L.-F., Newton, M. A., Li, Y., Thomson, J., Stewart, R., & Kendziorski, C. (2016) · Genome Biology · doi:10.1186/s13059-016-1077-y · Cited by 273
Self-citationTranscriptional 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
Self-citationA tiling-deletion-based genetic screen for cis-regulatory element identification in mammalian cells
Diao, Y., Fang, R., Li, B., Meng, Z., Yu, J., Qiu, Y., Lin, K. C., Huang, H., Liu, T., Marina, R. J., et al. (2017) · Nature Methods · doi:10.1038/nmeth.4264 · Cited by 259
Self-citationBroadly permissive intestinal chromatin underlies lateral inhibition and cell plasticity
Kim, T.-H., Li, F., Ferreiro-Neira, I., Ho, L.-L., Luyten, A., Nalapareddy, K., Long, H., Verzi, M., & Shivdasani, R. A. (2014) · Nature · doi:10.1038/nature12903 · Cited by 257
The interplay between DNA and histone methylation: molecular mechanisms and disease implications
Li, Y., Chen, X., & Lu, C. (2021) · The EMBO Reports · doi:10.15252/embr.202051803 · Cited by 223
Self-citationGenome-wide characterization of the routes to pluripotency
Hussein, S. M. I., Puri, M. C., Tonge, P. D., Benevento, M., Corso, A. J., Clancy, J. L., Mosbergen, R., Li, M., Lee, D.-S., Cloonan, N., et al. (2014) · Nature · doi:10.1038/nature14046 · Cited by 197
Guo, H., Zhu, P., Guo, F., Li, X., Wu, X., Fan, X., Wen, L., & Tang, F. (2015) · Nature Protocols · doi:10.1038/nprot.2015.039 · Cited by 188
Identification of Novel Long Noncoding RNAs Underlying Vertebrate Cardiovascular Development
Kurian, L., Aguirre, A., Sancho-Martinez, I., Benner, C., Hishida, T., Nguyen, T. B., Reddy, P., Nivet, E., Krause, M. N., Nelles, D. A., et al. (2015) · Circulation · doi:10.1161/circulationaha.114.013303 · Cited by 189
Brunetti, L., Gundry, M. C., & Goodell, M. A. (2017) · Cold Spring Harbor Perspectives in Medicine · doi:10.1101/cshperspect.a030320 · Cited by 186
Jaffe, A. E., Shin, J., Collado-Torres, L., Leek, J. T., Tao, R., Li, C., Gao, Y., Jia, Y., Maher, B. J., Hyde, T. M., et al. (2015) · Nature Neuroscience · doi:10.1038/nn.3898 · Cited by 156
Transposable elements in the mammalian embryo: pioneers surviving through stealth and service
Gerdes, P., Richardson, S. R., Mager, D. L., & Faulkner, G. J. (2016) · Genome Biology · doi:10.1186/s13059-016-0965-5 · Cited by 156
Tracing dynamic changes of DNA methylation at single cell resolution
Stelzer, Y., Shivalila, C. S., Soldner, F., Markoulaki, S., & Jaenisch, R. (2015) · Cell · doi:10.1016/j.cell.2015.08.046 · Cited by 141
Adeno-to-squamous transition drives resistance to KRAS inhibition in LKB1 mutant lung cancer
Tong, X., Patel, A. S., Kim, E., Li, H., Chen, Y., Li, S., Liu, S., Dilly, J., Kapner, K. S., Zhang, N., et al. (2024) · Cancer Cell · doi:10.1016/j.ccell.2024.01.012 · Cited by 142
Self-citationSenut, M.-C., Sen, A., Cingolani, P., Shaik, A., Land, S. J., & Ruden, D. M. (2014) · Toxicological Sciences · doi:10.1093/toxsci/kfu028 · Cited by 135
A new class of temporarily phenotypic enhancers identified by CRISPR/Cas9-mediated genetic screening
Diao, Y., Li, B., Meng, Z., Jung, I., Lee, A. Y., Dixon, J., Maliskova, L., Guan, K.-L., Shen, Y., & Ren, B. (2016) · Genome Research · doi:10.1101/gr.197152.115 · Cited by 122
Self-citationA unique role for DNA (hydroxy)methylation in epigenetic regulation of human inhibitory neurons
Kozlenkov, A., Li, J., Apontes, P., Hurd, Y. L., Byne, W. M., Koonin, E. V., Wegner, M., Mukamel, E. A., & Dracheva, S. (2018) · Science Advances · doi:10.1126/sciadv.aau6190 · Cited by 103
Charlet, J., Duymich, C. E., Lay, F. D., Mundbjerg, K., Dalsgaard Sørensen, K., Liang, G., & Jones, P. A. (2016) · Molecular Cell · doi:10.1016/j.molcel.2016.03.033 · Cited by 128
Glioblastoma epigenome profiling identifies SOX10 as a master regulator of molecular tumour subtype
Wu, Y., Fletcher, M., Gu, Z., Wang, Q., Costa, B., Bertoni, A., Man, K.-H., Schlotter, M., Felsberg, J., Mangei, J., et al. (2020) · Nature Communications · doi:10.1038/s41467-020-20225-w · Cited by 101
Self-citationKrebs, A. R., Dessus-Babus, S., Burger, L., & Schübeler, D. (2014) · eLife · doi:10.7554/elife.04094 · Cited by 81
Lactate-induced histone lactylation by p300 promotes osteoblast differentiation
Minami, E., Sasa, K., Yamada, A., Kawai, R., Yoshida, H., Nakano, H., Maki, K., & Kamijo, R. (2023) · PLOS ONE · doi:10.1371/journal.pone.0293676 · Cited by 73
Yen, A., & Kellis, M. (2015) · Nature Communications · doi:10.1038/ncomms8973 · Cited by 67
An integrated transcriptomic and epigenomic atlas of mouse primary motor cortex cell types
Yao, Z., Liu, H., Xie, F., Fischer, S., Booeshaghi, A. S., Adkins, R. S., Aldridge, A. I., Ament, S. A., Pinto-Duarte, A., Bartlett, A., et al. (2020) · doi:10.1101/2020.02.29.970558 · Cited by 397
Self-citationChromatin-state barriers enforce an irreversible mammalian cell fate decision
Blanco, M. A., Sykes, D. B., Gu, L., Wu, M., Petroni, R., Karnik, R., Wawer, M., Rico, J., Li, H., Jacobus, W. D., et al. (2021) · Cell Reports · doi:10.1016/j.celrep.2021.109967 · Cited by 45
Decoding the role of TET family dioxygenases in lineage specification
Wu, X., Li, G., & Xie, R. (2018) · Epigenetics & Chromatin · doi:10.1186/s13072-018-0228-7 · Cited by 43
Usp22 deficiency impairs intestinal epithelial lineage specification in vivo
Kosinsky, R. L., Wegwitz, F., Hellbach, N., Dobbelstein, M., Mansouri, A., Vogel, T., Begus-Nahrmann, Y., & Johnsen, S. A. (2015) · Oncotarget · doi:10.18632/oncotarget.5412 · Cited by 34
PRC2 clock: a universal epigenetic biomarker of aging and rejuvenation
Moqri, M., Cipriano, A., Nachun, D., Murty, T., de Sena Brandine, G., Rasouli, S., Tarkhov, A., Aberg, K. A., van den Oord, E., Zhou, W., et al. (2022) · doi:10.1101/2022.06.03.494609 · Cited by 22
Paldi, F., Szalay, M.-F., Dufau, S., Di Stefano, M., Reboul, H., Jost, D., Bantignies, F., & Cavalli, G. (2026) · Nature Genetics · doi:10.1038/s41588-025-02489-4 · Cited by 18
Lu, Z., Chen, C., Zhang, H., Li, B., Liu, Y., Guo, J., Xu, R., Shi, K., Ma, Q., Zhang, M., et al. (2025) · Nature Cancer · doi:10.1038/s43018-025-01031-z · Cited by 4
Self-citationCheng, C. C. Y., Cheung, M. F., Lee, A. Y., Wu, Q., Chow, S. H.-C., Ang, J. Y. J., Riquelme Medina, I., Lo, G., Wu, H., Yang, W., et al. (2025) · Communications Biology · doi:10.1038/s42003-025-09154-w · Cited by 3
Self-citation
Metadata
- Authors
- Xie, W., Schultz, M. D., Lister, R., Hou, Z., Rajagopal, N., Ray, P., Whitaker, J. W., Tian, S., Hawkins, R. D., Leung, D., Yang, H., Wang, T., Lee, A. Y., Swanson, S. A., Zhang, J., Zhu, Y., Kim, A., Nery, J. R., Urich, M. A., Kuan, S., Yen, C.-A., Klugman, S., Yu, P., Suknuntha, K., Propson, N. E., Chen, H., Edsall, L. E., Wagner, U., Li, Y., Ye, Z., Kulkarni, A., Xuan, Z., Chung, W.-Y., Chi, N. C., Antosiewicz-Bourget, J. E., Slukvin, I., Stewart, R., Zhang, M. Q., Wang, W., Thomson, J. A., Ecker, J. R., & Ren, B.
- Venue
- Cell
- Publisher
- Elsevier BV
- Published
- 2013-05
- Volume
- 153
- Issue
- 5
- Pages
- 1134-1148
- ISSN
- 0092-8674 (ISSN-L)
- OpenAlex
- W2157232603
- Cited by
- 735
- References
- 21
- FWCI
- 36.58
- Type
- journal article
- Language
- en
- Open access
- bronze
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.
