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THZ1 Alters RNA Polymerase Dynamics at the 5' and 3' Ends of Genes (GSE102243)

The t(8;21) is one of the most frequent chromosomal translocations associated with acute myeloid leukemia (AML). We found that t(8;21) AML were extremely sensitive to THZ1, which triggered apoptosis after only 4 hr. We used precision nuclear run-on transcription sequencing (PROseq) to define the global effects of THZ1 and other CDK inhibitors on RNA polymerase II dynamics. Inhibition of CDK7 using THZ1 caused wide-spread loss of promoter-proximal paused RNA polymerase. This loss of 5 pausing was associated with accumulation of polymerases in the body of a large number of genes. However, there were modest effects on genes regulated by super-enhancers. At the 3 ends of genes, treatment with THZ1 suppressed RNA polymerase read through at the end of the last exon, which resembled a phenotype associated with a mutant RNA polymerase with slower elongation rates. Consistent with this hypothesis, polyA site-sequencing (PolyA-seq) did not detect differences in polyA sites after THZ1 treatment. PROseq analysis after short treatments with THZ1 suggested that these 3 effects were due to altered CDK7 activity at the 5 end of long genes, and were likely to be due to slower rates of elongation. SOURCE: Scott Hiebert (scott.hiebert@vanderbilt.edu) - PRB 512 Vanderbilt University

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