Large conserved domains of low DNA methylation maintained by Dnmt3a

Mira Jeong; Deqiang Sun; Min Luo; Yun Huang; Grant A. Challen; Benjamin Rodriguez; Xiaotian Zhang; Lukas Chavez; Hui Wang; Rebecca Hannah; Sang Bae Kim; Liubin Yang; Myunggon Ko; Rui Chen; Berthold Göttgens; Ju Seog Lee; Preethi Gunaratne; Lucy A. Godley; Gretchen J. Darlington; Anjana Rao; Wei Li; Margaret A. Goodell

doi:10.1038/ng.2836

Large conserved domains of low DNA methylation maintained by Dnmt3a

Mira Jeong, Deqiang Sun, Min Luo, Yun Huang, Grant A. Challen, Benjamin Rodriguez, Xiaotian Zhang, Lukas Chavez, Hui Wang, Rebecca Hannah, Sang Bae Kim, Liubin Yang, Myunggon Ko, Rui Chen, Berthold Göttgens, Ju Seog Lee, Preethi Gunaratne, Lucy A. Godley, Gretchen J. Darlington, Anjana RaoWei Li, Margaret A. Goodell

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Abstract

Gains and losses in DNA methylation are prominent features of mammalian cell types. To gain insight into the mechanisms that promote shifts in DNA methylation and contribute to changes in cell fate, including malignant transformation, we performed genome-wide mapping of 5-methylcytosine and 5-hydroxymethylcytosine in purified mouse hematopoietic stem cells. We discovered extended regions of low methylation (canyons) that span conserved domains frequently containing transcription factors and are distinct from CpG islands and shores. About half of the genes in these methylation canyons are coated with repressive histone marks, whereas the remainder are covered by activating histone marks and are highly expressed in hematopoietic stem cells (HSCs). Canyon borders are demarked by 5-hydroxymethylcytosine and become eroded in the absence of DNA methyltransferase 3a (Dnmt3a). Genes dysregulated in human leukemias are enriched for canyon-associated genes. The new epigenetic landscape we describe may provide a mechanism for the regulation of hematopoiesis and may contribute to leukemia development.

Original language	English
Pages (from-to)	17-23
Number of pages	7
Journal	Nature Genetics
Volume	46
Issue number	1
DOIs	https://doi.org/10.1038/ng.2836
State	Published - Jan 2014

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Jeong, M., Sun, D., Luo, M., Huang, Y., Challen, G. A., Rodriguez, B., Zhang, X., Chavez, L., Wang, H., Hannah, R., Kim, S. B., Yang, L., Ko, M., Chen, R., Göttgens, B., Lee, J. S., Gunaratne, P., Godley, L. A., Darlington, G. J., ... Goodell, M. A. (2014). Large conserved domains of low DNA methylation maintained by Dnmt3a. Nature Genetics, 46(1), 17-23. https://doi.org/10.1038/ng.2836

@article{d5b3f839220a4829a1a367ed10f7aa82,

title = "Large conserved domains of low DNA methylation maintained by Dnmt3a",

abstract = "Gains and losses in DNA methylation are prominent features of mammalian cell types. To gain insight into the mechanisms that promote shifts in DNA methylation and contribute to changes in cell fate, including malignant transformation, we performed genome-wide mapping of 5-methylcytosine and 5-hydroxymethylcytosine in purified mouse hematopoietic stem cells. We discovered extended regions of low methylation (canyons) that span conserved domains frequently containing transcription factors and are distinct from CpG islands and shores. About half of the genes in these methylation canyons are coated with repressive histone marks, whereas the remainder are covered by activating histone marks and are highly expressed in hematopoietic stem cells (HSCs). Canyon borders are demarked by 5-hydroxymethylcytosine and become eroded in the absence of DNA methyltransferase 3a (Dnmt3a). Genes dysregulated in human leukemias are enriched for canyon-associated genes. The new epigenetic landscape we describe may provide a mechanism for the regulation of hematopoiesis and may contribute to leukemia development.",

author = "Mira Jeong and Deqiang Sun and Min Luo and Yun Huang and Challen, {Grant A.} and Benjamin Rodriguez and Xiaotian Zhang and Lukas Chavez and Hui Wang and Rebecca Hannah and Kim, {Sang Bae} and Liubin Yang and Myunggon Ko and Rui Chen and Berthold G{\"o}ttgens and Lee, {Ju Seog} and Preethi Gunaratne and Godley, {Lucy A.} and Darlington, {Gretchen J.} and Anjana Rao and Wei Li and Goodell, {Margaret A.}",

note = "Funding Information: We thank T. Chen, J.P. Issa, J. Gilbert and members of the Goodell laboratory for helpful discussions. This work was supported by US National Institutes of Health (NIH) grants AG036562, CA126752, DK092883, CA125123, DK084259 and AI07495, the Ellison Medical Foundation, Cancer Prevention Research Institute of Texas (CPRIT) grant RP110028 and the Samuel Waxman Foundation (M.A.G.): by CPRIT RP110471, NIH grant RO1HG007538 and DOD PC094421 (W.L.); and by grants CA151535 and CIRM RM1-01729 and Leukemia and Lymphoma Society award 6187-12 (A.R.). Y.H. and M.K. are supported by Leukemia and Lymphoma Society fellowships.",

year = "2014",

month = jan,

doi = "10.1038/ng.2836",

language = "English",

volume = "46",

pages = "17--23",

journal = "Nature Genetics",

issn = "1061-4036",

number = "1",

}

Jeong, M, Sun, D, Luo, M, Huang, Y, Challen, GA, Rodriguez, B, Zhang, X, Chavez, L, Wang, H, Hannah, R, Kim, SB, Yang, L, Ko, M, Chen, R, Göttgens, B, Lee, JS, Gunaratne, P, Godley, LA, Darlington, GJ, Rao, A, Li, W & Goodell, MA 2014, 'Large conserved domains of low DNA methylation maintained by Dnmt3a', Nature Genetics, vol. 46, no. 1, pp. 17-23. https://doi.org/10.1038/ng.2836

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AU - Jeong, Mira

AU - Sun, Deqiang

AU - Luo, Min

AU - Huang, Yun

AU - Challen, Grant A.

AU - Rodriguez, Benjamin

AU - Zhang, Xiaotian

AU - Chavez, Lukas

AU - Wang, Hui

AU - Hannah, Rebecca

AU - Kim, Sang Bae

AU - Yang, Liubin

AU - Ko, Myunggon

AU - Chen, Rui

AU - Göttgens, Berthold

AU - Lee, Ju Seog

AU - Gunaratne, Preethi

AU - Godley, Lucy A.

AU - Darlington, Gretchen J.

AU - Rao, Anjana

AU - Li, Wei

AU - Goodell, Margaret A.

N1 - Funding Information: We thank T. Chen, J.P. Issa, J. Gilbert and members of the Goodell laboratory for helpful discussions. This work was supported by US National Institutes of Health (NIH) grants AG036562, CA126752, DK092883, CA125123, DK084259 and AI07495, the Ellison Medical Foundation, Cancer Prevention Research Institute of Texas (CPRIT) grant RP110028 and the Samuel Waxman Foundation (M.A.G.): by CPRIT RP110471, NIH grant RO1HG007538 and DOD PC094421 (W.L.); and by grants CA151535 and CIRM RM1-01729 and Leukemia and Lymphoma Society award 6187-12 (A.R.). Y.H. and M.K. are supported by Leukemia and Lymphoma Society fellowships.

PY - 2014/1

Y1 - 2014/1

N2 - Gains and losses in DNA methylation are prominent features of mammalian cell types. To gain insight into the mechanisms that promote shifts in DNA methylation and contribute to changes in cell fate, including malignant transformation, we performed genome-wide mapping of 5-methylcytosine and 5-hydroxymethylcytosine in purified mouse hematopoietic stem cells. We discovered extended regions of low methylation (canyons) that span conserved domains frequently containing transcription factors and are distinct from CpG islands and shores. About half of the genes in these methylation canyons are coated with repressive histone marks, whereas the remainder are covered by activating histone marks and are highly expressed in hematopoietic stem cells (HSCs). Canyon borders are demarked by 5-hydroxymethylcytosine and become eroded in the absence of DNA methyltransferase 3a (Dnmt3a). Genes dysregulated in human leukemias are enriched for canyon-associated genes. The new epigenetic landscape we describe may provide a mechanism for the regulation of hematopoiesis and may contribute to leukemia development.

AB - Gains and losses in DNA methylation are prominent features of mammalian cell types. To gain insight into the mechanisms that promote shifts in DNA methylation and contribute to changes in cell fate, including malignant transformation, we performed genome-wide mapping of 5-methylcytosine and 5-hydroxymethylcytosine in purified mouse hematopoietic stem cells. We discovered extended regions of low methylation (canyons) that span conserved domains frequently containing transcription factors and are distinct from CpG islands and shores. About half of the genes in these methylation canyons are coated with repressive histone marks, whereas the remainder are covered by activating histone marks and are highly expressed in hematopoietic stem cells (HSCs). Canyon borders are demarked by 5-hydroxymethylcytosine and become eroded in the absence of DNA methyltransferase 3a (Dnmt3a). Genes dysregulated in human leukemias are enriched for canyon-associated genes. The new epigenetic landscape we describe may provide a mechanism for the regulation of hematopoiesis and may contribute to leukemia development.

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DO - 10.1038/ng.2836

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SP - 17

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JO - Nature Genetics

JF - Nature Genetics

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Large conserved domains of low DNA methylation maintained by Dnmt3a

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