Changcun Guo1,2,3, Chun-Chi Chang1,2,4, Matthew Wortham1,2,4, Lee H. Chen1,2,4, Dawn Kernagis5, Xiaoxia Qin6, Young‐Wook Cho7, Jen‐Tsan Chi6, Gerald A. Grant8,2,9, Roger E. McLendon1,2,4, Hai Yan1,2,4, Kai Ge10, Nickolas Papadopoulos11, Darell D. Bigner1,2,4, Yiping He1,2,4
1Department of Pathology
2Pediatric Brain Tumor Foundation Institute,
3The Preston Robert Tisch Brain Tumor Center at Duke, Pediatric Brain Tumor Foundation Institute, cDepartment of Pathology, Duke University, Durham, NC 27710, USA.
4aThe Preston Robert Tisch Brain Tumor Center at Duke,
5cDepartment of Pathology,
6dInstitute for Genome Sciences and Policy, and
7eLaboratory of Endocrinology and Receptor Biology, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892; and
8Department of Surgery, Duke University, Durham, NC 27710;
9fDepartment of Surgery, Duke University, Durham, NC 27710;
10Laboratory of Endocrinology and Receptor Biology, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892; and
11gLudwig Center for Cancer Genetics and Therapeutics, Sidney Kimmel Comprehensive Cancer Center, Baltimore, MD 21231
Tóm tắt
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.
