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

Changcun Guo, Chun Chi Chang, Matthew Wortham, Lee H. Chen, Dawn N. Kernagis, Xiaoxia Qin, Young Wook Cho, Jen Tsan Chi, Gerald A. Grant, Roger E. McLendon, Hai Yan, Kai Ge, Nickolas Papadopoulos, Darell D. Bigner, Yiping He

Research output: Contribution to journalArticle

Abstract

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.

Original languageEnglish (US)
Pages (from-to)17603-17608
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume109
Issue number43
DOIs
StatePublished - Oct 23 2012

Keywords

  • S100A gene cluster
  • Somatic targeting
  • Tumor suppressor

ASJC Scopus subject areas

  • General

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  • Cite this

    Guo, C., Chang, C. C., Wortham, M., Chen, L. H., Kernagis, D. N., Qin, X., Cho, Y. W., Chi, J. T., Grant, G. A., McLendon, R. E., Yan, H., Ge, K., Papadopoulos, N., Bigner, D. D., & He, Y. (2012). Global identification of MLL2-targeted loci reveals MLL2's role in diverse signaling pathways. Proceedings of the National Academy of Sciences of the United States of America, 109(43), 17603-17608. https://doi.org/10.1073/pnas.1208807109