title: The zinc finger protein ZNF658 regulates the transcription of genes involved in zinc homeostasis and affects ribosome biogenesis through the zinc transcriptional regulatory element.
abstract: We previously identified the ZTRE (zinc transcriptional regulatory element) in genes involved in zinc homeostasis and showed that it mediates transcriptional repression in response to zinc. We now report that ZNF658 acts at the ZTRE. ZNF658 was identified by matrix-assisted laser desorption ionization-time of flight mass spectrometry of a band excised after electrophoretic mobility shift assay using a ZTRE probe. The protein contains a KRAB domain and 21 zinc fingers. It has similarity with ZAP1 from Saccharomyces cerevisiae, which regulates the response to zinc restriction, including a conserved DNA binding region we show to be functional also in ZNF658. Small interfering RNA (siRNA) targeted to ZNF658 abrogated the zinc-induced, ZTRE-dependent reduction in SLC30A5 (ZnT5 gene), SLC30A10 (ZnT10 gene), and CBWD transcripts in human Caco-2 cells and the ability of zinc to repress reporter gene expression from corresponding promoter-reporter constructs. Microarray analysis of the effect of reducing ZNF658 expression by siRNA uncovered a large decrease in rRNA. We find that ZTREs are clustered within the 45S rRNA precursor. We also saw effects on expression of multiple ribosomal proteins. ZNF658 thus links zinc homeostasis with ribosome biogenesis, the most active transcriptional, and hence zinc-demanding, process in the cell. ZNF658 is thus a novel transcriptional regulator that plays a fundamental role in the orchestrated cellular response to zinc availability.
authors.affiliation: Institute for Cell and Molecular Biosciences, Newcastle University, Newcastle upon Tyne, United Kingdom Human Nutrition Research Centre, Newcastle University, Newcastle upon Tyne, United Kingdom.
authors.forename: Ogo A
authors.initials: OA
authors.lastname: Ogo
authors.affiliation: Institute for Cell and Molecular Biosciences, Newcastle University, Newcastle upon Tyne, United Kingdom Human Nutrition Research Centre, Newcastle University, Newcastle upon Tyne, United Kingdom.
authors.forename: John
authors.initials: J
authors.lastname: Tyson
authors.affiliation: Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, United Kingdom.
authors.forename: Simon J
authors.initials: SJ
authors.lastname: Cockell
authors.affiliation: School of Dental Sciences, Newcastle University, Newcastle upon Tyne, United Kingdom.
authors.forename: Alison
authors.initials: A
authors.lastname: Howard
authors.affiliation: School of Dental Sciences, Newcastle University, Newcastle upon Tyne, United Kingdom Human Nutrition Research Centre, Newcastle University, Newcastle upon Tyne, United Kingdom.
authors.forename: Ruth A
authors.initials: RA
authors.lastname: Valentine
authors.affiliation: Institute for Cell and Molecular Biosciences, Newcastle University, Newcastle upon Tyne, United Kingdom Human Nutrition Research Centre, Newcastle University, Newcastle upon Tyne, United Kingdom dianne.ford@ncl.ac.uk.
authors.forename: Dianne
authors.initials: D
authors.lastname: Ford
mesh_terms: D000595:Amino Acid Sequence; D001665:Binding Sites / Q000235:genetics; D018938:Caco-2 Cells; D045744:Cell Line, Tumor; D004268:DNA-Binding Proteins / Q000235:genetics; D015870:Gene Expression / Q000235:genetics; D006706:Homeostasis / Q000235:genetics*; D006801:Humans; D008969:Molecular Sequence Data; D011401:Promoter Regions, Genetic / Q000235:genetics; D050436:Regulatory Elements, Transcriptional / Q000235:genetics*; D012270:Ribosomes / Q000235:genetics*; D012441:Saccharomyces cerevisiae / Q000235:genetics; D029701:Saccharomyces cerevisiae Proteins / Q000235:genetics; D014158:Transcription, Genetic / Q000235:genetics*; D015032:Zinc / Q000378:metabolism*; D016335:Zinc Fingers / Q000235:genetics*
chemical_list: D004268:DNA-Binding Proteins; D029701:Saccharomyces cerevisiae Proteins; D015032:Zinc