Global identification of MLL2-targeted loci reveals MLL2's role in diverse signaling pathways

被引：81

作者：

Guo, Changcun ^{[1
,2
,3
]}

Chang, Chun-Chi ^{[1
,2
,3
]}

Wortham, Matthew ^{[1
,2
,3
]}

Chen, Lee H. ^{[1
,2
,3
]}

Kernagis, Dawn N. ^{[3
]}

Qin, Xiaoxia ^{[4
]}

Cho, Young-Wook ^{[6
]}

Chi, Jen-Tsan ^{[4
]}

Grant, Gerald A. ^{[1
,2
,5
]}

McLendon, Roger E. ^{[1
,2
,3
]}

Yan, Hai ^{[1
,2
,3
]}

Ge, Kai ^{[6
]}

Papadopoulos, Nickolas ^{[7
]}

Bigner, Darell D. ^{[1
,2
,3
]}

He, Yiping ^{[1
,2
,3
]}

机构：

[1] Duke Univ, Preston Robert Tisch Brain Tumor Ctr Duke, Durham, NC 27710 USA

[2] Duke Univ, Pediat Brain Tumor Fdn Inst, Durham, NC 27710 USA

[3] Duke Univ, Dept Pathol, Durham, NC 27710 USA

[4] Duke Univ, Inst Genome Sci & Policy, Durham, NC 27710 USA

[5] Duke Univ, Dept Surg, Durham, NC 27710 USA

[6] NIDDKD, Lab Endocrinol & Receptor Biol, NIH, Bethesda, MD 20892 USA

[7] Sidney Kimmel Comprehens Canc Ctr, Ludwig Ctr Canc Genet & Therapeut, Baltimore, MD 21231 USA

来源：

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA | 2012年 / 109卷 / 43期

关键词：

tumor suppressor; somatic targeting; S100A gene cluster; HISTONE H3K4 TRIMETHYLATION; B-CELL LYMPHOMA; SOMATIC MUTATIONS; CHROMATIN IMMUNOPRECIPITATION; METHYLTRANSFERASE ACTIVITY; ENDOGENOUS PROTEINS; ESTROGEN-RECEPTOR; MODIFYING GENES; LEUKEMIA-CELLS; TARGET GENES;

D O I：

10.1073/pnas.1208807109

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：

Myeloid/lymphoid or mixed-lineage leukemia (MLL)-family genes encode histone lysine methyltransferases that play important roles in epigenetic regulation of gene transcription. MLL genes are frequently mutated in human cancers. Unlike MLL1, MLL2 (also known as ALR/MLL4) and its homolog MLL3 are not well-understood. Specifically, little is known regarding the extent of global MLL2 involvement in the regulation of gene expression and the mechanism underlying its alterations in driving tumorigenesis. Here we profile the global loci targeted by MLL2. A combinatorial analysis of the MLL2 binding profile and gene expression in MLL2 wild-type versus MLL2-null isogenic cell lines identified direct transcriptional target genes and revealed the connection of MLL2 to multiple cellular signaling pathways, including the p53 pathway, cAMP-mediated signaling, and cholestasis signaling. In particular, we demonstrate that MLL2 participates in retinoic acid receptor signaling by promoting retinoic acid-responsive gene transcription. Our results present a genome-wide integrative analysis of the MLL2 target loci and suggest potential mechanisms underlying tumorigenesis driven by MLL2 alterations.

引用

页码：17603 / 17608

页数：6

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