We set an absolute 2. 5 fold change and p value of 0. 01 for TSA responsive Belinostat molecular weight genes, similarly, CBHA responsive genes were re filtered through an absolute 3. 5 fold change and a p value of 0. 01. These statistical maneuvers reduced TSA regulated genes to 157 and 114, at 6h and 24h post treatment. Of these, 52 genes were up regulated at 6h and 104 genes down regulated. At 24h treat ment 52 genes were up regulated and 62 genes were down regulated. A more stringent statistical analysis yielded 147 and 249 genes for CBHA treatment at 6h and 24h, respectively. At 6h treatment of CBHA 82 genes were up regulated and 65 genes down regulated. At 24h treatment 90 genes were up regulated and 159 genes were down regulated.
The initial analysis of the merged datasets by IPA revealed that although CBHA and TSA elicited unique signatures of gene expression, the two pan HDAC inhi bitors also impinged on numerous common gene targets at 6h and 24h post treatment. We also observed that genes in Clusters A through C were generally up regulated by both HDACIs, in contrast, expression of most of the mRNAs contained in Clusters D through F was repressed by both CBHA and TSA. Next, we combined the top seven IPA networks of TSA specific DEGs at 6h and 24h to reveal the hierarchy of the potential gene networks in the actions of the two pan HDACIs. The DEGs seen after 6h treatment with TSA revealed the existence of TGFB TNF and IFN�� specific gene networks. These cytokine hubs were connected with signaling kinases such as PTEN PI3K AKT and MAPK, and transcription factors, and.
We should note here that the inflammatory cytokine hubs are connected to genes that were either induced or suppressed by TSA. Thus, TNF spe cific hub was connected to HDAC 7, cardiotrophin, GSK-3 MyoD and Myogenin, all of which were down regulated, in contrast, the expression of geminin was induced by TSA. Similarly, the IFN�� specific hub is connected to both TSA inducible and TSA suppressible genes. Finally, PTEN specific hub is connected to two microtubule associated kinases MAST1 and LIMK1 that were up regulated by TSA and a transcription factor that was down regulated in TSA treated H9c2 cells post 6h treatment. These data are consistent with our earlier report showing that the expression of PTEN was highly induced by CBHA in H9c2 cells and in response to both CBHA and TSA in the intact heart. A continued exposure to TSA for 24h led to apparent consolidation of the TGFB and TNF specific gene networks. However, in contrast to a dominant involvement of PTEN PI3K AKT signaling seen at 6h, at 24h, MAPK sig naling connected with TGFB and TNF specific hubs was prominent.
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