Reciprocal stabilization of transcription factor binding integrates two signaling pathways to regulate fission yeast fbp1 transcription

Transcriptional regulation, a pivotal biological process by which cells adapt to environmental fluctuations, is achieved by the binding of transcription factors to target sequences in a sequence-specific manner. However, how transcription factors recognize the correct target from amongst the numerous candidates in a genome has not been fully elucidated. We here show that, in the fission-yeast fbp1 gene, when transcription factors bind to target sequences in close proximity, their binding is reciprocally stabilized, thereby integrating distinct signal transduction pathways. The fbp1 gene is massively induced upon glucose starvation by the activation of two transcription factors, Atf1 and Rst2, mediated via distinct signal transduction pathways. Atf1 and Rst2 bind to the upstream-activating sequence 1 region, carrying two binding sites located 45 bp apart. Their binding is reciprocally stabilized due to the close proximity of the two target sites, which destabilizes the independent binding of Atf1 or Rst2. Tup11/12 (Tup-family co-repressors) suppress independent binding. These data demonstrate a previously unappreciated mechanism by which two transcription-factor binding sites, in close proximity, integrate two independent-signal pathways, thereby behaving as a hub for signal integration.

A rare case of fructose-1,6-bisphosphatase deficiency: a delayed diagnosis story

ObjectivesFructose-1,6-bisphosphatase deficiency (FBPase deficiency, OMIM 229700) is an early-onset rare genetic disorder caused by mutations in the FBP1 gene.Case presentationOur patient was 17-years-old when she was diagnosed with the disease. Initial sequencing analysis with Ion Torrent technology failed to detect the gross deletion that covered complete exon 2 (c.-24-26_170 + 5192del) of FBP1 gene and caused the delay in diagnosis. Deletion was then detected when sequencing was performed in an Illumina MiSeq platform.ConclusionsThis case emphasizes the importance of sequencing data analysis for precise diagnosis of rare diseases and therapy planning.

Significance of Methylation of FBP1 Gene in Non-Small Cell Lung Cancer

Because NSCLC has poor overall prognosis and is frequently diagnosed at later stage, we aimed to seek novel diagnosis biomarkers or therapy target of the disease in this study. Fructose-1,6-bisphosphatase 1 (FBP1) is a rate-limiting enzyme in gluconeogenesis, which was usually lost in NSCLC due to abnormal methylation in promoter DNA sequence. The clinical data indicated that the methylation rate in FBP1 gene promoter was negatively related to the overall survival of the NSCLC patients. DNA methylation transferase inhibitor 5-aza treatment could significantly increase both expression levels of mRNA and protein in A549 cell line. On the other hand, silence of FBP1 in H460 cell line by using specific siRNA against FBP1 dramatically improved the cell proliferation and cell migration according to the date of FACS and transwell assays. All these findings implied the important roles of FBP1 expression in lung cancer development and progression and the potential use of the methylation status detected in FBP1 promoter region as a novel predictor for prognosis and therapeutic target for NSCLC patients.

Fructose-1,6-bisphosphatase deficiency caused by a novel homozygous Alu element insertion in the FBP1 gene and delayed diagnosis

Fructose-1,6-bisphosphatase (FBPase) enzyme deficiency is one of the treatable autosomal recessive inherited metabolic disorders. If diagnosed early, FBPase deficiency has a favorable prognosis. We report the clinical and biochemical findings of a 9.5-year-old female child with FBPase deficiency. FBPase deficiency is caused by a homozygousArthrobacter luteus (Alu)insertion in theFBP1gene, reported for the first time.

Fission Yeast Tup1-Like Repressors Repress Chromatin Remodeling at thefbp1+ Promoter and theade6-M26Recombination Hotspot

Chromatin remodeling plays crucial roles in the regulation of gene expression and recombination. Transcription of the fission yeast fbp1+ gene and recombination at the meiotic recombination hotspot ade6-M26 (M26) are both regulated by cAMP responsive element (CRE)-like sequences and the CREB/ATF-type transcription factor Atf1•Pcr1. The Tup11 and Tup12 proteins, the fission yeast counterparts of the Saccharomyces cerevisiae Tup1 corepressor, are involved in glucose repression of the fbp1+ transcription. We have analyzed roles of the Tup1-like corepressors in chromatin regulation around the fbp1+ promoter and the M26 hotspot. We found that the chromatin structure around two regulatory elements for fbp1+ was remodeled under derepressed conditions in concert with the robust activation of fbp1+ transcription. Strains with tup11Δ tup12Δ double deletions grown in repressed conditions exhibited the chromatin state associated with wild-type cells grown in derepressed conditions. Interestingly, deletion of rst2+, encoding a transcription factor controlled by the cAMP-dependent kinase, alleviated the tup11Δ tup12Δ defects in chromatin regulation but not in transcription repression. The chromatin at the M26 site in mitotic cultures of a tup11Δ tup12Δ mutant resembled that of wild-type meiotic cells. These observations suggest that these fission yeast Tup1-like corepressors repress chromatin remodeling at CRE-related sequences and that Rst2 antagonizes this function.