Genome-wide analysis reveals conserved and divergent features of Notch1/RBPJ binding in human and murine T-lymphoblastic leukemia cells

被引:197
作者
Wang, Hongfang [2 ]
Zou, James [1 ]
Zhao, Bo [3 ,4 ]
Johannsen, Eric [3 ,4 ]
Ashworth, Todd [2 ]
Wong, Hoifung [2 ]
Pear, Warren S. [5 ]
Schug, Jonathan [6 ]
Blacklow, Stephen C. [7 ]
Arnett, Kelly L. [7 ]
Bernstein, Bradley E. [8 ]
Kieff, Elliott [3 ,4 ]
Aster, Jon C. [2 ]
机构
[1] Harvard Univ, Sch Engn & Appl Sci, Cambridge, MA 02138 USA
[2] Brigham & Womens Hosp, Dept Pathol, Boston, MA 02115 USA
[3] Brigham & Womens Hosp, Dept Microbiol & Mol Genet, Boston, MA 02115 USA
[4] Brigham & Womens Hosp, Dept Med, Boston, MA 02115 USA
[5] Univ Penn, Sch Med, Dept Pathol, Philadelphia, PA 19104 USA
[6] Univ Penn, Sch Med, Dept Genet, Philadelphia, PA 19104 USA
[7] Dana Farber Canc Inst, Dept Canc Biol, Boston, MA 02115 USA
[8] Massachusetts Gen Hosp, Howard Hughes Med Inst, Dept Pathol, Boston, MA 02114 USA
基金
美国国家科学基金会; 美国国家卫生研究院;
关键词
CSL; lymphoma; transformation; TRANSCRIPTION FACTOR-BINDING; BARR-VIRUS EBNA2; BIDIRECTIONAL PROMOTERS; HUMAN STAF/ZNF143; C-MYC; ACTIVATION; LINEAGE; GROWTH; SPECIFICATION; CHROMATIN;
D O I
10.1073/pnas.1109023108
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
Notch1 regulates gene expression by associating with the DNA-binding factor RBPJ and is oncogenic in murine and human T-cell progenitors. Using ChIP-Seq, we find that in human and murine T-lymphoblastic leukemia (TLL) genomes Notch1 binds preferentially to promoters, to RBPJ binding sites, and near imputed ZNF143, ETS, and RUNX sites. ChIP-Seq confirmed that ZNF143 binds to similar to 40% of Notch1 sites. Notch1/ZNF143 sites are characterized by high Notch1 and ZNF143 signals, frequent cobinding of RBPJ (generally through sites embedded within ZNF143 motifs), strong promoter bias, and relatively low mean levels of activating chromatin marks. RBPJ and ZNF143 binding to DNA is mutually exclusive in vitro, suggesting RBPJ/Notch1 and ZNF143 complexes exchange on these sites in cells. K-means clustering of Notch1 binding sites and associated motifs identified conserved Notch1-RUNX, Notch1-ETS, Notch1-RBPJ, Notch1-ZNF143, and Notch1-ZNF143-ETS clusters with different genomic distributions and levels of chromatin marks. Although Notch1 binds mainly to gene promoters, similar to 75% of direct target genes lack promoter binding and are presumably regulated by enhancers, which were identified near MYC, DTX1, IGF1R, IL7R, and the GIMAP cluster. Human and murine TLL genomes also have many sites that bind only RBPJ. Murine RBPJ-only sites are highly enriched for imputed REST (a DNA-binding transcriptional repressor) sites, whereas human RPBJ-only sites lack REST motifs and are more highly enriched for imputed CREB sites. Thus, there is a conserved network of cis-regulatory factors that interacts with Notch1 to regulate gene expression in TLL cells, as well as unique classes of divergent RBPJ-only sites that also likely regulate transcription.
引用
收藏
页码:14908 / 14913
页数:6
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