Chromatin modifications induced by PML-RARalpha repress critical targets in leukemogenesis as analyzed by ChIP-Chip.

Abstract

The translocation t(15;17) generates the chimeric PML-RARalpha transcription factor that is the initiating event of acute promyelocytic leukemia. A global view of PML-RARalpha transcriptional functions was obtained by genome-wide binding and chromatin modification analyses combined with genome-wide expression data. Chromatin immunoprecipitation (ChIP)-chip experiments identified 372 direct genomic PML-RARalpha targets. A subset of these was confirmed in primary acute promyelocytic leukemia. Direct PML-RARalpha targets include regulators of global transcriptional programs as well as critical regulatory genes for basic cellular functions such as cell-cycle control and apoptosis. PML-RARalpha binding universally led to HDAC1 recruitment, loss of histone H3 acetylation, increased tri-methylation of histone H3 lysine 9, and unexpectedly increased trimethylation of histone H3 lysine 4. The binding of PML-RARalpha to target promoters and the resulting histone modifications resulted in mRNA repression of functionally relevant genes. Taken together, our results reveal that the transcription factor PML-RARalpha regulates key cancer-related genes and pathways by inducing a repressed chromatin formation on its direct genomic target genes.

• Authors: Claudia Hoemme, Abdul Peerzada, Gerhard Behre, Yipeng Wang, Michael McClelland, Kay Nieselt, Matthias Zschunke, Christine Disselhoff, Shuchi Agrawal, Fabienne Isken, Nicola Tidow, Wolfgang E Berdel, Hubert Serve, Carsten Müller-Tidow
• Journal: Blood (Blood) Vol. 111 Issue 5 Pg. 2887-95 (Mar 01 2008) ISSN: 0006-4971 [Print] United States
• PMID: 18024792 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)

Chemical References

• Chromatin
• Histones
• Neoplasm Proteins
• Oncogene Proteins, Fusion
• RNA, Messenger
• promyelocytic leukemia-retinoic acid receptor alpha fusion oncoprotein

Topics

• Chromatin (metabolism)
• Chromatin Immunoprecipitation
• Gene Expression Profiling
• Gene Expression Regulation, Leukemic
• Genome, Human (genetics)
• Histones (metabolism)
• Humans
• Leukemia (genetics, pathology)
• Neoplasm Proteins (genetics, metabolism)
• Oncogene Proteins, Fusion (genetics, metabolism)
• Promoter Regions, Genetic (genetics)
• Protein Binding
• RNA, Messenger (genetics, metabolism)
• Reproducibility of Results
• Reverse Transcriptase Polymerase Chain Reaction
• U937 Cells