Abstract
We recently reported that adenovirus E1A enhances MYC association with the NuA4/Tip60 histone acetyltransferase (HAT) complex to activate a panel of genes enriched for DNA replication and cell cycle. Genes from this panel are highly expressed in examined cancer cell lines when compared to normal fibroblasts. To further understand gene regulation in cancer by MYC and the NuA4 complex, we performed RNA-seq analysis of MD-MB231 breast cancer cells following knockdown of MYC or Tip60 - the HAT enzyme of the NuA4 complex. We identify here a panel of 424 genes, referred to as MYC-Tip60 co-regulated panel (MTcoR), that are dependent on both MYC and Tip60 for expression and likely co-regulated by MYC and the NuA4 complex. The MTcoR panel is most significantly enriched in genes involved in cell cycle and/or DNA replication. In contrast, genes repressed by shMYC but not by shTip60 (224 genes) have a low significance of enrichment in identifiable biological processes other than cell cycle and DNA replication. Genes repressed by shTip60 but not by shMYC (102 genes) have no significant identifiable gene enrichment. We propose that MYC cooperates with the NuA4 complex to activate the MTcoR panel of genes to promote DNA replication and cell cycle.
Highlights
The proto-oncogene product MYC is a transcription factor over-expressed in many cancers [1,2,3]
Among the MNP300 panel genes previously selected for analysis due to their roles in cell cycle and DNA replication [16], FEN1 and CCNE2 were most efficiently repressed by all four shRNA clones (Figure 1), and may be co-regulated by MYC and the NuA4 complex
The co-repression of the selected MNP300 panel genes mediated by shMYC and shTip60 suggests that these shMYC and shTip60 clones are suitable for MYC and Tip60 knockdown and subsequent global analysis of their effects on gene repression
Summary
The proto-oncogene product MYC is a transcription factor over-expressed in many cancers [1,2,3]. The human NuA4 complex has up to 20 subunits [10] with a core HAT enzyme Tip to acetylate primarily histones H2 and H4 [11,12,13]. It is involved in chromatin remodeling, gene activation, and DNA damage repair [10, 14, 15]. Activation of the MNP300 panel requires E1A enhanced MYC association with the NuA4 complex as well as E1A targeting of p300/CBP [16]. Selected genes from the MNP300 panel are highly expressed in the three examined cancer cell lines compared to normal fibroblasts [16], suggesting involvement of MYC association with the NuA4 complex in activation of the MNP300 panel in cancer cells
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