Global Identification of MLL2-targeted Loci Reveals MLL2's Role in Diverse Signaling Pathways

Overview

Journal Proc Natl Acad Sci U S A

Specialty Science

Date 2012 Oct 10

PMID 23045699

Citations 61

Authors

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

Affiliations

Soon will be listed here.

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.

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