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

A global view of PML-RARα transcriptional functions was obtained by genome-wide binding and chromatin modification analyses, combined with genome wide expression data. Complete Abstract: The translocation t(15;17) generates the chimeric PML-RARα transcription factor that is the initiating event of acute promyelocytic leukemia. A global view of PML-RARα transcriptional functions was obtained by genome-wide binding and chromatin modification analyses, combined with genome wide expression data. ChIP-chip experiments identified 372 direct genomic PML-RARα targets. A subset of these was confirmed in primary acute promyelocytic leukemia. Direct PML-RARá 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-RARα binding universally led to HDAC1 recruitment, loss of histone H3 acetylation, increased tri-methylation of histone H3 lysine 9 and unexpectedly increased tri-methylation of histone H3 lysine 4. The binding of PMLRARα 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-RARα regulates key cancer related genes and pathways by inducing a repressed chromatin formation on its direct genomic target genes. Keywords: ChIP on Chip Overall design: U937 transfected with an inducible PML-RARα/empty vecor were induced, harvested and Chromatin-Ips for PML, AcH3 followed by microarray hybridasation were carried out. For detailed procedures see Hoemme et al. "Chromatin modifications induced by PML-RARalpha repress critical targets in leukemogenesis as analyzed by ChIP-Chip"