TFIID is the main sequence-specific DNA-binding component of the RNA polymerase II (Pol II) transcriptional machinery. It is a multiprotein complex composed of the TATA-binding protein (TBP) and TBP-associated factors (TAF11s). Here we report the cloning and characterization of a novel human TBPassociated factor, hTAF1168. It contains a consensus RNA-binding domain (RNP-CS) and binds not only RNA, but also single stranded (ss) DNA. hTAF1168 shares extensive sequence similarity with TLS/FUS and EWS, two human nuclear RNA-binding prooncoproteins which are products of genes commonly translocated in human sarcomas. Like hTAF1168, TLS/ FUS is also associated with a sub-population of TFIID complexes chromatographically separable from those containing hTAF1168. Therefore, these RNA and/or ssDNA-binding proteins may play specific roles during transcription initiation at distinct promoters. Moreover, we demonstrate that hTAF1168 co-purifies also with the human RNA polymerase II and can enter the preinitiation complex together with Pol II.

The molecular events during nongenotoxic carcinogenesis and their temporal order are poorly understood but thought to include long-lasting perturbations of gene expression. Here, we have investigated the temporal sequence of molecular and pathological perturbations at early stages of phenobarbital (PB) mediated liver tumor promotion in vivo. Molecular profiling (mRNA, microRNA [miRNA], DNA methylation, and proteins) of mouse liver during 13 weeks of PB treatment revealed progressive increases in hepatic expression of long noncoding RNAs and miRNAs originating from the Dlk1-Dio3 imprinted gene cluster, a locus that has recently been associated with stem cell pluripotency in mice and various neoplasms in humans. PB induction of the Dlk1-Dio3 cluster noncoding RNA (ncRNA) Meg3 was localized to glutamine synthetase-positive hypertrophic perivenous hepatocytes, suggesting a role for β-catenin signaling in the dysregulation of Dlk1-Dio3 ncRNAs. The carcinogenic relevance of Dlk1-Dio3 locus ncRNA induction was further supported by in vivo genetic dependence on constitutive androstane receptor and β-catenin pathways. Our data identify Dlk1-Dio3 ncRNAs as novel candidate early biomarkers for mouse liver tumor promotion and provide new opportunities for assessing the carcinogenic potential of novel compounds.

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