Large conserved domains of low DNA methylation maintained by Dnmt3a

被引：266

作者：

Jeong, Mira ^{[1
]}

Sun, Deqiang ^{[2
,3
]}

Luo, Min ^{[1
]}

Huang, Yun ^{[4
]}

Challen, Grant A. ^{[1
]}

Rodriguez, Benjamin ^{[2
,3
]}

Zhang, Xiaotian ^{[1
]}

Chavez, Lukas ^{[4
]}

Wang, Hui ^{[5
]}

Hannah, Rebecca ^{[6
,7
]}

Kim, Sang-Bae ^{[8
]}

Yang, Liubin ^{[1
]}

Ko, Myunggon ^{[4
]}

Chen, Rui

Goettgens, Berthold ^{[6
,7
]}

Lee, Ju-Seog ^{[8
]}

Gunaratne, Preethi ^{[9
,10
]}

Godley, Lucy A. ^{[11
]}

Darlington, Gretchen J. ^{[12
]}

Rao, Anjana ^{[4
]}

Li, Wei ^{[2
,3
]}

Goodell, Margaret A. ^{[1
]}

机构：

[1] Baylor Coll Med, Dept Pediat & Mol & Human Genet, Stem Cells & Regenerat Med Ctr, Houston, TX 77030 USA

[2] Baylor Coll Med, Dan L Duncan Canc Ctr, Div Biostat, Houston, TX 77030 USA

[3] Baylor Coll Med, Dept Mol & Cellular Biol, Houston, TX 77030 USA

[4] La Jolla Inst Allergy & Immunol, Div Signaling & Gene Express, La Jolla, CA USA

[5] Baylor Coll Med, Human Genome Sequencing Ctr, Houston, TX 77030 USA

[6] Univ Cambridge, Cambridge Inst Med Res, Dept Hematol, Cambridge, England

[7] Univ Cambridge, Wellcome Trust & Med Res Council Cambridge, Stem Cell Inst, Cambridge, England

[8] Univ Texas MD Anderson Canc Ctr, Div Canc Med, Dept Syst Biol, Houston, TX 77030 USA

[9] Baylor Coll Med, Dept Pathol, Houston, TX 77030 USA

[10] Univ Houston, Dept Biol & Biochem, Houston, TX USA

[11] Univ Chicago, Dept Med, Chicago, IL 60637 USA

[12] Baylor Coll Med, Huffington Ctr Aging, Houston, TX 77030 USA

来源：

NATURE GENETICS | 2014年 / 46卷 / 01期

基金：

美国国家卫生研究院; 英国生物技术与生命科学研究理事会;

关键词：

CANCER GENOME; 5-HYDROXYMETHYLCYTOSINE; MUTATIONS; CHROMATIN; 5-METHYLCYTOSINE; METHYLOME; GENES; CELLS; TET2;

D O I：

10.1038/ng.2836

中图分类号：

Q3 [遗传学];

学科分类号：

071007 ; 090102 ;

摘要：

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.

引用

页码：17 / +

页数：10

共 47 条

[1] Genetic characterization of TET1, TET2, and TET3 alterations in myeloid malignancies [J].

Abdel-Wahab, Omar ;

Mullally, Ann ;

Hedvat, Cyrus ;

Garcia-Manero, Guillermo ;

Patel, Jay ;

Wadleigh, Martha ;

Malinge, Sebastien ;

Yao, JinJuan ;

Kilpivaara, Outi ;

Bhat, Rukhmi ;

Huberman, Kety ;

Thomas, Sabrena ;

Dolgalev, Igor ;

Heguy, Adriana ;

Paietta, Elisabeth ;

Le Beau, Michelle M. ;

Beran, Miloslav ;

Tallman, Martin S. ;

Ebert, Benjamin L. ;

Kantarjian, Hagop M. ;

Stone, Richard M. ;

Gilliland, D. Gary ;

Crispino, John D. ;

Levine, Ross L. .

BLOOD, 2009, 114 (01) :144-147

[2] Transcriptional features of genomic regulatory blocks [J].

Akalin, Altuna ;

Fredman, David ;

Arner, Erik ;

Dong, Xianjun ;

Bryne, Jan Christian ;

Suzuki, Harukazu ;

Daub, Carsten O. ;

Hayashizaki, Yoshihide ;

Lenhard, Boris .

GENOME BIOLOGY, 2009, 10 (04)

[3] The Drosophila Gene Disruption Project: Progress Using Transposons With Distinctive Site Specificities [J].

Bellen, Hugo J. ;

Levis, Robert W. ;

He, Yuchun ;

Carlson, Joseph W. ;

Evans-Holm, Martha ;

Bae, Eunkyung ;

Kim, Jaeseob ;

Metaxakis, Athanasios ;

Savakis, Charalambos ;

Schulze, Karen L. ;

Hoskins, Roger A. ;

Spradling, Allan C. .

GENETICS, 2011, 188 (03) :731-U341

[4] A bivalent chromatin structure marks key developmental genes in embryonic stem cells [J].

Bernstein, BE ;

Mikkelsen, TS ;

Xie, XH ;

Kamal, M ;

Huebert, DJ ;

Cuff, J ;

Fry, B ;

Meissner, A ;

Wernig, M ;

Plath, K ;

Jaenisch, R ;

Wagschal, A ;

Feil, R ;

Schreiber, SL ;

Lander, ES .

CELL, 2006, 125 (02) :315-326

[5] Regional Activation of the Cancer Genome by Long-Range Epigenetic Remodeling [J].

Bert, Saul A. ;

Robinson, Mark D. ;

Strbenac, Dario ;

Statham, Aaron L. ;

Song, Jenny Z. ;

Hulf, Toby ;

Sutherland, Robert L. ;

Coolen, Marcel W. ;

Stirzaker, Clare ;

Clark, Susan J. .

CANCER CELL, 2013, 23 (01) :9-22

[6]

BIRD A, 1985, CELL, V40, P91, DOI 10.1016/0092-8674(85)90312-5

[7] Quantitative Sequencing of 5-Methylcytosine and 5-Hydroxymethylcytosine at Single-Base Resolution [J].

Booth, Michael J. ;

Branco, Miguel R. ;

Ficz, Gabriella ;

Oxley, David ;

Krueger, Felix ;

Reik, Wolf ;

Balasubramanian, Shankar .

SCIENCE, 2012, 336 (6083) :934-937

[8] Dnmt3a is essential for hematopoietic stem cell differentiation [J].

Challen, Grant A. ;

Sun, Deqiang ;

Jeong, Mira ;

Luo, Min ;

Jelinek, Jaroslav ;

Berg, Jonathan S. ;

Bock, Christoph ;

Vasanthakumar, Aparna ;

Gu, Hongcang ;

Xi, Yuanxin ;

Liang, Shoudan ;

Lu, Yue ;

Darlington, Gretchen J. ;

Meissner, Alexander ;

Issa, Jean-Pierre J. ;

Godley, Lucy A. ;

Li, Wei ;

Goodell, Margaret A. .

NATURE GENETICS, 2012, 44 (01) :23-U43

[9] Consolidation of the cancer genome into domains of repressive chromatin by long-range epigenetic silencing (LRES) reduces transcriptional plasticity [J].

Coolen, Marcel W. ;

Stirzaker, Clare ;

Song, Jenny Z. ;

Statham, Aaron L. ;

Kassir, Zena ;

Moreno, Carlos S. ;

Young, Andrew N. ;

Varma, Vijay ;

Speed, Terence P. ;

Cowley, Mark ;

Lacaze, Paul ;

Kaplan, Warren ;

Robinson, Mark D. ;

Clark, Susan J. .

NATURE CELL BIOLOGY, 2010, 12 (03) :235-U37

[10] A rapid micro chromatin immunoprecipitation assay (μChIP) [J].

Dahl, John Arne ;

Collas, Philippe .

NATURE PROTOCOLS, 2008, 3 (06) :1032-1045

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