Cell type-specific DNA methylation patterns in the human breast

被引：174

作者：

Bloushtain-Qimron, Noga ^{[1
,8
,9
]}

Yao, Jun ^{[1
,3
]}

Snyder, Eric L. ^{[1
,3
]}

Shipitsin, Michail ^{[1
,3
]}

Campbell, Lauren L. ^{[1
,5
]}

Mani, Sendurai A. ^{[10
]}

Hua, Min ^{[1
,3
]}

Chen, Haiyan ^{[2
,7
]}

Ustyansky, Vadim ^{[11
]}

Antosiewicz, Jessica E. ^{[12
]}

Argani, Pedram ^{[8
,9
]}

Halushka, Marc K. ^{[13
]}

Thomson, James A. ^{[12
]}

Pharoah, Paul ^{[14
]}

Porgador, Angel ^{[8
,9
]}

Sukumar, Saraswati

Parsons, Ramon ^{[15
]}

Richardson, Andrea L. ^{[4
,6
]}

Stampfer, Martha R. ^{[16
]}

Gelman, Rebecca S. ^{[2
]}

Nikolskaya, Tatiana ^{[11
,17
]}

Nikolsky, Yuri ^{[11
]}

Polyak, Kornelia ^{[1
,3
,5
]}

机构：

[1] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA

[2] Dana Farber Canc Inst, Dept Biostat & Computat Biol, Boston, MA 02115 USA

[3] Harvard Univ, Sch Med, Dept Med, Boston, MA 02115 USA

[4] Harvard Univ, Sch Med, Dept Pathol, Boston, MA 02115 USA

[5] Harvard Univ, Sch Med, Program Biol & Biomed Sci, Boston, MA 02115 USA

[6] Brigham & Womens Hosp, Dept Pathol, Boston, MA 02115 USA

[7] Harvard Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02115 USA

[8] Ben Gurion Univ Negev, Fac Hlth Sci, Dept Microbiol & Immunol, IL-84105 Beer Sheva, Israel

[9] Ben Gurion Univ Negev, Canc Res Ctr, IL-84105 Beer Sheva, Israel

[10] Whitehead Inst Biomed Res, Cambridge, MA 02142 USA

[11] GeneGo Inc, St Joseph, MI 49085 USA

[12] Univ Wisconsin, Sch Med, Madison, WI 53706 USA

[13] Johns Hopkins Univ, Sch Med, Baltimore, MD 21231 USA

[14] Can Res UK, Cambridge CB2 0RE, England

[15] Columbia Univ, Dept Med, New York, NY 10032 USA

[16] Univ Calif Berkeley, Lawrence Berkeley Lab, Div Life Sci, Berkeley, CA 94720 USA

[17] Russian Acad Sci, NI Vavilov Gen Genet Res Inst, Moscow 117809, Russia

来源：

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA | 2008年 / 105卷 / 37期

基金：

美国国家卫生研究院;

关键词：

cancer; differentiation; progenitor; stem cell;

D O I：

10.1073/pnas.0805206105

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

Cellular identity and differentiation are determined by epigenetic programs. The characteristics of these programs in normal human mammary epithelium and their similarity to those in stem cells are unknown. To begin investigating these issues, we analyzed the DNA methylation and gene expression profiles of distinct subpopulations of mammary epithelial cells by using MSDK (methylation-specific digital karyotyping) and SAGE (serial analysis of gene expression). We identified discrete cell-type and differentiation state-specific DNA methylation and gene expression patterns that were maintained in a subset of breast carcinomas and correlated with clinically relevant tumor subtypes. CD44+ cells were the most hypomethylated and highly expressed several transcription factors with known stem cell function including HOXA10 and TCF3. Many of these genes were also hypomethylated in BMP4-treated compared with undifferentiated human embryonic stem (ES) cells that we analyzed by MSDK for comparison. Further highlighting the similarity of epigenetic programs of embryonic and mammary epithelial cells, genes highly expressed in CD44+ relative to more differentiated CD24+ cells were significantly enriched for Suz12 targets in ES cells. The expression of FOXC1, one of the transcription factors hypomethylated and highly expressed in CD44+ cells, induced a progenitor-like phenotype in differentiated mammary epithelial cells. These data suggest that epigenetically controlled transcription factors play a key role in regulating mammary epithelial cell phenotypes and imply similarities among epigenetic programs that define progenitor cell characteristics.

引用

页码：14076 / 14081

页数：6

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