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BBA - Gene Regulatory Mechanisms (v.1819, #1)

Title Page/Sections Editors (pp. i).

Reviewer Acknowledgment (pp. iii-iv).

PPARγ and NF-κB regulate the gene promoter activity of their shared repressor, TNIP1 by Igor Gurevich; Carmen Zhang; Priscilla C. Encarnacao; Charles P. Struzynski; Sarah E. Livings; Brian J. Aneskievich (pp. 1-15).

Human TNFAIP3 interacting protein 1 (TNIP1) has diverse functions including support of HIV replication through its interaction with viral Nef and matrix proteins, reduction of TNFα-induced signaling through its interaction with NF-κB pathway proteins, and corepression of agonist-bound retinoic acid receptors and peroxisome proliferator-activated receptors (PPAR). The wide tissue distribution of TNIP1 provides the opportunity to influence numerous cellular responses in these roles and defining control of TNIP1 expression would be central to improved understanding of its impact on cell function. We cloned 6kb of the human TNIP1 promoter and performed predictive and functional analyses to identify regulatory elements. The promoter region proximal to the transcription start site is GC-rich without a recognizable TATA box. In contrast to this proximal ~500bp region, 6kb of the promoter increased reporter construct constitutive activity over five-fold. Throughout the 6kb length, in silico analysis identified several potential binding sites for both constitutive and inducible transcription factors; among the latter were candidate NF-κB binding sequences and peroxisome proliferator response elements (PPREs). We tested NF-κB and PPAR regulation of the endogenous TNIP1 gene and cloned promoter by expression studies, electrophoretic mobility shift assays, and chromatin immunoprecipitations. We validated NF-κB sites in the TNIP1 promoter proximal and distal regions as well as one PPRE in the distal region. The ultimate control of the TNIP1 promoter is likely to be a combination of constitutive transcription factors and those subject to activation such as NF-κB and PPAR.► Six kilobases of the human TNIP1 promoter were cloned and examined in silico. ► Functional NF-κB and PPAR sites have been identified in the human TNIP1 promoter. ► NF-κB and PPARγ bind to the endogenous TNIP1 promoter. ► The TNIP1 promoter PPRE functions in an orientation-independent manner. ► TNIP1 expression is likely to vary as abundance and activity of NF-κB and PPAR change.

Keywords: Abbreviations; Nef; negative factor of HIV; NR; nuclear receptor; PP; peroxisome proliferator; PPRE; PP response element; RIP; receptor interacting protein; RQ; relative quantitation; scZ; scrambled sequence of Z element; TNIP1; TNFAIP3-interacting protein 1; TNFAIP3; TNF-α-induced protein 3; TRO; troglitazonePPAR; NF-κB; Promoter; Transcriptional regulation; Response element

The mitotic Clb cyclins are required to alleviate HIR-mediated repression of the yeast histone genes at the G1/S transition by Amit Dipak Amin; Dessislava K. Dimova; Monica E. Ferreira; Nidhi Vishnoi; Leandria C. Hancock; Mary Ann Osley; Philippe Prochasson (pp. 16-27).

The histone genes are an important group of cell cycle regulated genes whose transcription is activated during the G1/S transition and repressed in early G1, late S, and G2/M. The HIR complex, comprised of Hir1, Hir2, Hir3 and Hpc2, regulates three of the four histone gene loci. While relief of repression at the G1/S boundary involves the HIR complex, as well as other cofactors, the mechanism by which this derepression occurs remains unknown. To better understand how transcriptional repression contributes to periodic expression in the cell cycle, we sought to identify the cell cycle signals required to alleviate HIR-mediated repression of the histone genes. By measuring histone gene transcription in strains with various combinations of clb mutations, we found that the mitotic Clb1/Clb2 cyclins are required to alleviate Hir-mediated repression during the G1/S transition and that Clb2 physically interacts with the HIR complex. While the HIR complex regulates histone gene transcription in combination with two other histone H3/H4 chaperones, Asf1 and Rtt106, our data demonstrate that the mitotic Clb cyclins are necessary to specifically alleviate the repressive action of the HIR complex itself in order to allow proper expression of the histone genes in late G1/early S phase.Display Omitted► Histone gene transcription is dependent upon the mitotic cyclins Clb1 and Clb2. ► Clb1 and Clb2 alleviate HIR-mediated repression of the histone genes at G1/S. ► SWI/SNF recruitment is not affected by the absence of the Clb cyclins. ► Clb2 physically interacts with the HIR complex. ► Clb1 and Clb2 have only a minor effect on repression exerted by Rtt106 and Asf1.

Keywords: Clb cyclin; HIR complex; Asf1; Rtt106; Histone gene; Cell cycle

FOXM1: From cancer initiation to progression and treatment by Chuay-Yeng Koo; Kyle W. Muir; Eric W.-F. Lam (pp. 28-37).

The Forkhead box protein M1 (FOXM1) transcription factor is a regulator of myriad biological processes, including cell proliferation, cell cycle progression, cell differentiation, DNA damage repair, tissue homeostasis, angiogenesis and apoptosis. Elevated FOXM1 expression is found in cancers of the liver, prostate, brain, breast, lung, colon, pancreas, skin, cervix, ovary, mouth, blood and nervous system, suggesting it has an integral role in tumorigenesis. Recent research findings also place FOXM1 at the centre of cancer progression and drug sensitivity. In this review the involvement of FOXM1 in various aspects of cancer, in particular its role and regulation within the context of cancer initiation, progression, and cancer drug response, will be summarised and discussed.► The FOXM1 transcription factor is a regulator of a broad range of biological processes. ► Elevated and deregulated FOXM1 expression is found in a wide spectrum of cancers. ► FOXM1 also plays a central role in cancer initiation, progression and anti-cancer drug resistance. ► This review summarises the role and regulation of FOXM1 in various aspects of cancer.

Keywords: FOXM1; Chemotherapy; Cancer; Function; Regulation

Functional characterization of the human translocator protein (18kDa) gene promoter in human breast cancer cell lines by Amani Batarseh; Keith D. Barlow; Daniel B. Martinez-Arguelles; Vassilios Papadopoulos (pp. 38-56).

The translocator protein (18kDa; TSPO) is a mitochondrial drug- and cholesterol-binding protein that has been implicated in several processes, including steroidogenesis, cell proliferation, and apoptosis. Expression of the human TSPO gene is elevated in several cancers. To understand the molecular mechanisms that regulate TSPO expression in human breast cancer cells, the TSPO promoter was identified, cloned, and functionally characterized in poor-in-TSPO hormone-dependent, non-aggressive MCF-7 cells and rich-in-TSPO hormone-independent, aggressive, and metastatic MDA-MB-231 breast cancer cells. RNA ligase-mediated 5′-rapid amplification of cDNA ends analysis indicated transcription initiated at multiple sites downstream of a GC-rich promoter that lacks functional TATA and CCAAT boxes. Deletion analysis indicated that the region from −121 to +66, which contains five putative regulatory sites known as GC boxes, was sufficient to induce reporter activity up to 24-fold in MCF-7 and nearly 120-fold in MDA-MB-231 cells. Electrophoretic mobility shift and chromatin immunoprecipitation assays indicated that Sp1, Sp3 and Sp4 bind to these GC boxes in vitro and to the endogenous TSPO promoter. Silencing of Sp1, Sp3 and Sp4 gene expression reduced TSPO levels. In addition, TSPO expression was epigenetically regulated at one or more of the identified GC boxes. Disruption of the sequence downstream of the main start site of TSPO differentially regulated TSPO promoter activity in MCF-7 and MDA-MB-231 cells, indicating that essential elements contribute to its differential expression in these cells. Taken together, these experiments constitute the first in-depth functional analysis of the human TSPO gene promoter and its transcriptional regulation.► Regulation of TSPO expression in human breast cancer cells depends on many factors. ► Sp1, Sp3 and Sp4 regulation for constitutive TSPO expression through GC3 promoter region. ► Epigenetic modification of the proximal promoter, at the GC3 site, and the first exon. ► Differential regulation of TSPO promoter in non-aggressive and aggressive cancer cells. ► Understanding its regulation provides a TSPO-mediated cancer therapeutic approach.

Keywords: Abbreviations; HBC; human breast cancer; HMEC; human mammary epithelial cells; TSPO; translocator Protein (18; kDa); ChIP; chromatin immunoprecipitation; TSA; Trichostatin A; AZA; 5-Azacytidine; Sp/KLF; Specificity Protein/Krüppel-like factorTSPO; Breast cancer; Metastasis; Sp1; Sp3; Epigenetics

FTZ-F1 and FOXL2 up-regulate catfish brain aromatase gene transcription by specific binding to the promoter motifs by P. Sridevi; R.K. Chaitanya; Aparna Dutta-Gupta; B. Senthilkumaran (pp. 57-66).

Cytochrome P450 aromatase (cyp19) catalyzes the conversion of androgens into estrogens. Teleosts have distinct, ovarian specific ( cyp19a1a) and brain specific ( cyp19a1b) cyp19 genes. Previous studies in teleosts demonstrated regulation of cyp19a1a expression by the NR5A nuclear receptor subfamily as well as a fork head transcription factor, FOXL2. In the present study, we investigated the involvement of fushi tarazu factor 1, FTZ-F1, a NR5A subfamily member, and FOXL2 in the regulation of cyp19a1b expression in brain of the air-breathing catfish, Clarias gariepinus. Based on the synchronous expression pattern of cyp19a1b, FTZ-F1 and FOXL2 in the brain, we isolated the 5′ upstream region of cyp19a1b to analyse regulatory motifs. Promoter motif analysis revealed FTZ-F1/NR5A1 and FOXL2 binding nucleotide sequences. Transient transfection studies showed that FTZ-F1 and FOXL2 together enhanced the transcriptional activity of cyp19a1b gene in mammalian cell lines. Mutation in either of their putative binding sites within the cyp19a1b promoter abolished this effect. Electrophoretic gel mobility shift experiments indicated that FTZ-F1 and FOXL2 proteins bind to the synthesized radio-labelled oligomers used as probes and mobility shifted upon addition of their respective antibodies. Chromatin immunoprecipitation assay confirmed the binding of both these transcription factors to their corresponding cis-acting elements in the upstream region of cyp19a1b. To our knowledge, this study is the first report on the transcriptional regulation of cyp19a1b by FTZ-F1 and FOXL2 in a teleost fish. ► FTZ-F1, FOXL2 and cyp19a1b exhibit synchronous expression pattern in teleost brain ► FTZ-F1 and FOXL2 binding elements identified in the cyp19a1b core promoter ► FTZ-F1 and FOXL2 up-regulate cyp19a1b gene in a cooperative manner ► First report on the involvement of FTZ-F1 and FOXL2 in the regulation of cyp19a1b

Keywords: Cytochrome P450 aromatase; cyp19a1b; FTZ-F1; FOXL2; Transcriptional regulation; Teleosts

The interaction between MYB proteins and their target DNA binding sites by Michael B. Prouse; Malcolm M. Campbell (pp. 67-77).

Members of the MYB family of transcription factors are found in all eukaryotic lineages, where they function to regulate either fundamental cellular processes, or specific facets of metabolism or cellular differentiation. MYB transcription factors regulate these processes through modulation of transcription at target genes, to which they bind in a sequence-specific manner. Over the past decades, insights have been gained into the molecular interactions between MYB proteins and their cognate DNA targets. This review focuses on those insights, the emergence of common themes in DNA binding by diverse MYB family members. The review also considers gaps in the current knowledge of MYB–DNA interactions, particularly for plant MYB proteins, and how emerging techniques that examine protein–DNA interactions can fill these gaps.► MYB transcription factors play a role in regulating diverse transcriptional events in eukaryotes. ► Much is known about the DNA-binding specificity of R1R2R3-MYB proteins from animals. ► Despite their importance in plants, there is limited information about the DNA-binding specificities of the diverse plant R2R3-MYB proteins. ► New methods will expand the characterisation of MYB-DNA interactions, filling gaps in knowledge about these important transcription factors.

Keywords: Abbreviations; R; MYB repeat; AMV; avian myeloblastosis virus; C1; COLORED1; locus; MBS; MYB binding site; EMSA; electrophoretic mobility-shift assay; AGRIS; Arabidopsis; gene regulatory information server; PLACE; Plant cis-acting regulatory elements database; TRANSFAC; Transcription factor database; UTR; untranslated regions; ChIP-chip; chromatin immunoprecipitation on chip; ChIP-seq; chromatin immunoprecipitation followed by high throughput sequencing; PDB; Protein data bank; TRFL; TRF1/2-Like genes; IBP; indicator binding protein group; SMH; single MYB histone group; WER; WEREWOLF; K; _d; dissociation constant; MSA; M phase-specific activator element; TF; transcription factor; SNP; sodium nitroprusside; GSNO; S; -nitrosoglutathione; CAST; cyclic amplification and selection of targets; SELEX; systematic evolution of ligands by exponential enrichment; FLP; FOUR LIPS; GL3; GLABRA3; GL1; GLABRA1; bHTH; basic helix–turn–helix; GR; glucocorticoid receptor; CPC; CAPRICE; WBS; WER-binding site; IFN-g; human interferon-g; LCR; locus control regionMYB; Transcription factor; DNA binding sites; Transcriptional regulation; Molecular modelling

Two mutations in the C-terminal domain of influenza virus RNA polymerase PB2 enhance transcription by enhancing cap-1 RNA binding activity by Shijian Zhang; Qiang Wang; Jinlan Wang; Kiyohisa Mizumoto; Tetsuya Toyoda (pp. 78-83).

Influenza virus RNA polymerase (RdRp) PB2 is the cap-1 binding subunit and determines host range and pathogenicity. The mutant human influenza virus RdRp containing PB2 D701N and D701N/S714R demonstrated enhanced replicon activity in mammalian cells. We investigated the influence of these mutations on RdRp activity. Cap-1-dependent transcription activities of D701N/S714R, D701N, and S714R were 348.1±6.2%, 146.4±11%, and 250.1±0.8% of that of the wild type (wt), respectively. Replication activity of these mutants for complimentary RNA to viral RNA ranged from 44% to 53% of that of the wt. Cap-1 RNA-binding activities of D701N/S714R, D701N, and S714R were 262±25%, 257±34%, and 315±9.6% of that of the wt, respectively, and their cap-dependent endonuclease activities were similar to that of the wt. These mutations did not affect template RNA-binding activities. D701N and S714R mutations enhanced transcription by enhancing cap-1 RNA-binding activity, but they may exhibit decreased efficiency of priming by the cap-1 primer. These mutations at the C-terminal domain of PB2 may affect its cap-binding domain.► Influenza virus RNA polymerase PB2 is the cap-1 binding subunit. ► PB2 D701N, and D701N/S714R enhanced replicon activity in mammalian cells. ► These mutations enhanced cap-1 dependent transcription in vitro. ► These mutations enhanced cap-1 RNA binding. ► These mutations did not affect the cap-dependent nuclease activity.

Keywords: Abbreviations; HA; hemagglutinin; HPAIV; highly pathogenic avian influenza virus; M1; matrix protein 1; NA; neuraminidase; NEP; nuclear export protein; NP; nucleoprotein; NS1; non-structural protein 1; PAGE; polyacrylamide gel electrophoresis; PEI; polyethyleneimine; RdRp; RNA polymerase; S-OIV; novel swine-origin influenza virus; TLC; thin-layer chromatography; cRNA; complementary RNA; nts; nucleotides; vRNA; viral RNA; wt; wild typeInfluenza virus; RNA polymerase; PB2; Transcription; cap-1 RNA binding; cap-dependent nuclease

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BBA - Gene Regulatory Mechanisms (v.1819, #1)