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

The translocation t(15;17) generates the chimeric PML-RAR alpha transcription factor that is the initiating event of acute promyelocytic leukemia. A global view of PML-RAR alpha 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-RAR alpha targets. A subset of these was confirmed in primary acute promyelocytic leukemia. Direct PML-RAR alpha. 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-RAR alpha binding universally led to HDAC1 recruitment, loss of histone H3 acetylation, increased trimethylation of histone H3 lysine 9, and unexpectedly increased trimethylation of histone H3 lysine 4. The binding of PML-RAR alpha to target promoters and the result ing histone modifications resulted in mRNA repression of functionally relevant genes. Taken together, our results reveal that the transcription factor PML-RAR alpha regulates key cancer-related genes and pathways by inducing a repressed chromatin formation on its direct genomic target genes.