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Comprehensive methylome map of lineage commitment from haematopoietic progenitors
Open accessAbstract
Epigenetic modifications must underlie lineage-specific differentiation as terminally differentiated cells express tissue-specific genes, but their DNA sequence is unchanged. Haematopoiesis provides a well-defined model to study epigenetic modifications during cell-fate decisions, as multipotent progenitors (MPPs) differentiate into progressively restricted myeloid or lymphoid progenitors. Although DNA methylation is critical for myeloid versus lymphoid differentiation, as demonstrated by the myeloerythroid bias in Dnmt1 hypomorphs, a comprehensive DNA methylation map of haematopoietic progenitors, or of any multipotent/oligopotent lineage, does not exist. Here we examined 4.6 million CpG sites throughout the genome for MPPs, common lymphoid progenitors (CLPs), common myeloid progenitors (CMPs), granulocyte/macrophage progenitors (GMPs), and thymocyte progenitors (DN1, DN2, DN3). Marked epigenetic plasticity accompanied both lymphoid and myeloid restriction. Myeloid commitment involved less global DNA methylation than lymphoid commitment, supported functionally by myeloid skewing of progenitors following treatment with a DNA methyltransferase inhibitor. Differential DNA methylation correlated with gene expression more strongly at CpG island shores than CpG islands. Many examples of genes and pathways not previously known to be involved in choice between lymphoid/myeloid differentiation have been identified, such as Arl4c and Jdp2. Several transcription factors, including Meis1, were methylated and silenced during differentiation, indicating a role in maintaining an undifferentiated state. Additionally, epigenetic modification of modifiers of the epigenome seems to be important in haematopoietic differentiation. Our results directly demonstrate that modulation of DNA methylation occurs during lineage-specific differentiation and defines a comprehensive map of the methylation and transcriptional changes that accompany myeloid versus lymphoid fate decisions.
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Cites
The earliest thymic progenitors for T cells possess myeloid lineage potential
Bell, J. J., & Bhandoola, A. (2008) · Nature · doi:10.1038/nature06840 · Cited by 460
Adult T-cell progenitors retain myeloid potential
Wada, H., Masuda, K., Satoh, R., Kakugawa, K., Ikawa, T., Katsura, Y., & Kawamoto, H. (2008) · Nature · doi:10.1038/nature06839 · Cited by 368
Cited by
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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
DNA methylation arrays as surrogate measures of cell mixture distribution
Houseman, E. A., Accomando, W. P., Koestler, D. C., Christensen, B. C., Marsit, C. J., Nelson, H. H., Wiencke, J. K., & Kelsey, K. T. (2012) · BMC Bioinformatics · doi:10.1186/1471-2105-13-86 · Cited by 3,175
DNA methylation: roles in mammalian development
Smith, Z. D., & Meissner, A. (2013) · Nature Reviews Genetics · doi:10.1038/nrg3354 · Cited by 3,045
Figueroa, M. E., Abdel-Wahab, O., Lu, C., Ward, P. S., Patel, J., Shih, A., Li, Y., Bhagwat, N., Vasanthakumar, A., Fernandez, H. F., et al. (2010) · Cancer Cell · doi:10.1016/j.ccr.2010.11.015 · Cited by 2,766
Epigenetic memory in induced pluripotent stem cells
Kim, K., Doi, A., Wen, B., Ng, K., Zhao, R., Cahan, P., Kim, J., Aryee, M. J., Ji, H., Ehrlich, L. I. R., et al. (2010) · Nature · doi:10.1038/nature09342 · Cited by 2,313
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Metadata
- Authors
- Ji, H., Ehrlich, L. I. R., Seita, J., Murakami, P., Doi, A., Lindau, P., Lee, H., Aryee, M. J., Irizarry, R. A., Kim, K., Rossi, D. J., Inlay, M. A., Serwold, T., Karsunky, H., Ho, L., Daley, G. Q., Weissman, I. L., & Feinberg, A. P.
- Venue
- Nature
- Published
- 2010-08-15
- Volume
- 467
- Issue
- 7313
- Pages
- 338-342
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- OpenAlex
- W2053856108
- Cited by
- 636
- References
- 2
- FWCI
- 25.64
- Type
- journal article
- Language
- en
- Open access
- green
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- Ji, H., Ehrlich, L. I. R., Seita, J., Murakami, P., Doi, A., Lindau, P., Lee, H., Aryee, M. J., Irizarry, R. A., Kim, K., Rossi, D. J., Inlay, M. A., Serwold, T., Karsunky, H., Ho, L., Daley, G. Q., Weissman, I. L., & Feinberg, A. P. (2010). Comprehensive methylome map of lineage commitment from haematopoietic progenitors. Nature. https://doi.org/10.1038/nature09367
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