SET domain containing 7(SETD7), a member of histone methyltransferases, is abnormally expressed in multiple tumor types. However, the biological function and underlying molecular mechanism of SETD7 in clear cell renal cell carcinoma (ccRCC) remain unclear. Here, we explored the biological effects of SETD7-TAF7-CCNA2 axis on proliferation and metastasis in ccRCC. We identified both SETD7 and TAF7 were up-regulated and significantly promoted the proliferation and migration of ccRCC cells. Concurrently, there was a significant positive correlation between the expression of SETD7 and TAF7, and the two were colocalized in the nucleus. Mechanistically, SETD7 methylates TAF7 at K5 and K300 sites, resulting in the deubiquitination and stabilization of TAF7. Furthermore, re-expression of TAF7 could partially restore SETD7 knockdown inhibited ccRCC cells proliferation and migration. In addition, TAF7 transcriptionally activated to drive the expression of cyclin A2 (CCNA2). And more importantly, the methylation of TAF7 at K5 and K300 sites exhibited higher transcriptional activity of CCNA2, which promotes formation and progression of ccRCC. Our findings reveal a unique mechanism that SETD7 mediated TAF7 methylation in regulating transcriptional activation of CCNA2 in ccRCC progression and provide a basis for developing effective therapeutic strategies by targeting members of SETD7-TAF7-CCNA2 axis.

The recognition of core promoter sequences by the general transcription factor TFIID is the first step in the process of RNA polymerase II (Pol II) transcription initiation. Metazoan holo-TFIID is composed of the TATA binding protein (TBP) and of 13 TBP associated factors (TAFs). Inducible Taf7 knock out (KO) results in the formation of a Taf7-less TFIID complex, while Taf10 KO leads to serious defects within the TFIID assembly pathway. Either TAF7 or TAF10 depletions correlate with the detected TAF occupancy changes at promoters, and with the distinct phenotype severities observed in mouse embryonic stem cells or mouse embryos. Surprisingly however, under either Taf7 or Taf10 deletion conditions, TBP is still associated to the chromatin, and no major changes are observed in nascent Pol II transcription. Thus, partially assembled TFIID complexes can sustain Pol II transcription initiation, but cannot replace holo-TFIID over several cell divisions and/or development.

OBJECTIVE: Genetic etiology of idiopathic male infertility is enigmatic owing to involvement of multiple gene regulatory networks in spermatogenesis process. Any change in optimal function of the transcription factors involved in this process owing to polymorphisms/mutations may increase the risk of infertility. We investigated polymorphisms/mutations of spermatogenic transcription regulators TAF7 and RFX2 and analysed their association with incidence of azoospermia among the men from West Bengal, India.
METHODS: Genotyping was carried by Sanger\'s dideoxy sequencing of 130 azoospermic men who were detected negative in Y chromosome microdeletion screening and 140 healthy controls. Association study was done by suitable statistical methods. In silico analysis was performed to infer the intuitive damaging effects of detected variants at transcripts and protein level.
RESULTS: We found significant association of TAF7 C16T (MW827584 G > A), RFX2 562delT (MZ560629delA), rs11547633 A > C, rs17606721 A > G, MW827583 C > T, and MZ379836 C > T variants with the incidence of azoospermia. In silico analysis predicted that the variants either alter the natural splice junctions of the transcript or cause probable damage in the structure of proteins of respective genes.
CONCLUSIONS: Polymorphisms/mutations of TAF7 and RFX2 genes increase risk of male infertility in Bengali population. The novel variants may be used as markers for male infertility screening in ART practise.

TATA-binding protein-associated factor 7 (TAF7), a dissociable component of the general transcription factor IID (TFIID), plays a role as a check-point regulator at the step of RNA polymerase II (Pol II) transcription initiation. Here, we focused on the role of TAF7 in heat-shocked cells, where its expression is induced by heat shock factor HSF1. TAF7 is a phosphoprotein, and the phosphorylation status is related to its interaction with TFIID and to its stability controlled by the ubiquitin-proteasome pathway. TAF7 is necessary for the prolonged expression of heat shock protein genes and for efficient recovery of heat-shocked cells. During sustained transcription, TAF7, presumably its TFIID-independent form, binds the promoter and enhances the levels of Pol II at the gene body but not the promoter. These results showed the novel function of TAF7 that is necessary for the transition from initiation to elongation in multiple-round transcription.

Recognition of gene promoters by RNA polymerase II is mediated by general transcription factor IID (TFIID), which has been thought to be a static complex and to play a passive role in the regulation of gene expression under the instruction of gene-specific transcription factors. Here we show that transforming growth factor β (TGF-β) induced degradation of the TFIID subunit TAF7 in cultured mouse mammary epithelial cells and that this effect was required for proliferative arrest in response to TGF-β stimulation. TGF-β stimulated transcription of the gene for the ubiquitin ligase TRIM26, which was shown to ubiquitylate TAF7 and thereby to target it for proteasomal degradation. Sustained exposure of cells to TGF-β resulted in recovery from proliferative arrest in association with amplification of the Myc proto-oncogene, with MYC inhibiting TRIM26 induction by TGF-β. Our data thus show that TFIID is not simply a general mediator of transcription but contributes to the regulation of transcription in response to cell stimulation, playing a key role in the cytostatic function of TGF-β.

The Major Histocompatibility Complex (MHC) class II transactivator (CIITA) mediates activated immune responses and its deficiency results in the Type II Bare Lymphocyte Syndrome. CIITA is a transcriptional co-activator that regulates γ-interferon-activated transcription of MHC class I and class II genes. It is also a functional homolog of TAF1, a component of the general transcription factor complex TFIID. TAF1 and CIITA both possess intrinsic acetyltransferase (AT) activity that is required for transcription initiation. In response to induction by γ-interferon, CIITA and it\'s AT activity bypass the requirement for TAF1 AT activity. TAF1 also has kinase activity that is essential for its function. However, no similar activity has been identified for CIITA thus far. Here we report that CIITA, like TAF1, is a serine-threonine kinase. Its substrate specificity parallels, but does not duplicate, that of TAF1 in phosphorylating the TFIID component TAF7, the RAP74 subunit of the general transcription factor TFIIF and histone H2B. Like TAF1, CIITA autophosphorylates, affecting its interaction with TAF7. Additionally, CIITA phosphorylates histone H2B at Ser36, a target of TAF1 that is required for transcription during cell cycle progression and stress response. However, unlike TAF1, CIITA also phosphorylates all the other histones. The identification of this novel kinase activity of CIITA further clarifies its role as a functional homolog of TAF1 which may operate during stress and γ-IFN activated MHC gene transcription.

TAF7, a component of the TFIID complex, controls the first steps of transcription. It interacts with and regulates the enzymatic activities of transcription factors that regulate RNA polymerase II progression. Its diverse functions in transcription initiation are consistent with its essential role in cell proliferation.