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

Changcun Guo1, Chun-Chi Chang, Matthew Wortham

  • 1The Preston Robert Tisch Brain Tumor Center at Duke, Pediatric Brain Tumor Foundation Institute, cDepartment of Pathology, Duke University, Durham, NC 27710, USA.

Proceedings of the National Academy of Sciences of the United States of America
|October 10, 2012
PubMed

Insights

Myeloid/lymphoid or mixed-lineage leukemia 2 (MLL2) regulates gene expression and is implicated in cancer. This study maps MLL2 targets genome-wide, revealing its role in key cellular pathways and retinoic acid signaling.

Area of Science:

  • Epigenetics
  • Molecular Biology
  • Cancer Genomics

Background:

  • Myeloid/lymphoid or mixed-lineage leukemia (MLL)-family genes are crucial for epigenetic regulation.
  • MLL genes, particularly MLL2 (ALR/MLL4) and MLL3, are frequently mutated in cancers but remain poorly understood.
  • The global role of MLL2 in gene expression and its contribution to tumorigenesis require further investigation.

Purpose of the Study:

  • To profile the global loci targeted by MLL2.
  • To identify direct transcriptional target genes of MLL2.
  • To elucidate the mechanisms by which MLL2 alterations contribute to tumorigenesis.

Main Methods:

  • Genome-wide profiling of MLL2 target loci.
  • Combinatorial analysis of MLL2 binding and gene expression data.
  • Comparison of MLL2 wild-type versus MLL2-null isogenic cell lines.

Main Results:

  • MLL2 directly regulates multiple cellular signaling pathways, including p53, cAMP-mediated, and cholestasis signaling.
  • MLL2 plays a significant role in retinoic acid receptor signaling by promoting retinoic acid-responsive gene transcription.
  • Identification of direct transcriptional targets provides insights into MLL2's function.

Conclusions:

  • MLL2 is a key epigenetic regulator involved in diverse cellular signaling pathways.
  • MLL2 alterations may drive tumorigenesis through disruption of these pathways, including retinoic acid signaling.
  • This study provides a genome-wide view of MLL2 targets, advancing our understanding of its role in cancer.

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