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A bacterial-like FadR transcription factor regulates fatty acid metabolism in the archaeal model organism Sulfolobus acidocaldarius
Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
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(English)Manuscript (preprint) (Other academic)
Abstract [en]

In accordance with the important biological roles of fatty acids, their metabolism is under complex regulation in bacteria and eukaryotes. In contrast, although certain archaea also appear to metabolize fatty acids, nothing is known about the regulation of the underlying pathways in these organisms. Here we show that the crenarchaeon Sulfolobus acidocaldarius harbors a bacterial-type TetR-family transcriptional regulator FadRSa and that it is involved in regulation of fatty acid metabolism. Functional and structural analyses show that the regulator binds semi-palindromic recognition sites in two distinct operator-dependent binding modes and that binding of fatty acyl-CoA molecules causes dissociation of FadRSa-DNA complexes by inducing conformational changes in the protein. Curiously, despite the similarity in overall structure and mechanisms between FadRSa and bacterial TetR-family FadR regulators, we reveal a fundamentally different acyl-CoA binding mode that suggests convergent evolution. Genome-wide transcriptomic and FadRSa-specific chromatin immunoprecipitation analyses further demonstrate that the transcription factor acts as a local repressor of a gene cluster comprising 23 open reading frames that encode lipases, beta-oxidation enzymes and acetyl-CoA acetyltransferases. We conclude that lipid degradation and fatty acid metabolism in S. acidocaldarius is subject to an acyl-CoA responsive transcriptional repression by a homolog of bacterial TetR-family FadR proteins of which the regulatory mechanism suggests that the regulated gene cluster minimally has a catabolic function.

Keywords [en]
Archaea, crenarchaeon, Sulfolobus acidocaldarius, TetR-family transcriptional regulator, fatty acid metabolism
National Category
Microbiology
Research subject
Molecular Bioscience
Identifiers
URN: urn:nbn:se:su:diva-153317OAI: oai:DiVA.org:su-153317DiVA, id: diva2:1187329
Available from: 2018-03-03 Created: 2018-03-03 Last updated: 2018-03-20Bibliographically approved
In thesis
1. Transcription regulation and growth phase transition in hyperthermoacidophilic archaea
Open this publication in new window or tab >>Transcription regulation and growth phase transition in hyperthermoacidophilic archaea
2018 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Organisms from the domain Archaea are ubiquitously represented on our planet and encompass diverse fascinating organisms. The genus Sulfolobus belonging to the phylum Crenarchaeota including hyperthermoacidophilic strains that grow optimally at 65-85°C and pH 2-3. These organisms have been used as model organisms for thermophiles to investigate archaeal DNA replication, transcription, translation, cell cycle, etc.

The focus of this thesis is on the study of archaeal specific transcription factors (TFs) as well as transcriptome changes during growth phase transition of the hyperthermoacidophilic archaeons Sulfolobus acidocaldarius and Sulfolobus solfataricus, respectively, to expand our knowledge on archaeal transcription regulation and growth phase adaptation.

In paper 1, we studied the genome-wide binding sites of BarR, which is a β-alanine responsive Lrp family TF that activates the expression of β-alanine aminotransferase located in a divergent operon in S. acidocaldarius. Chromatin immunoprecipitation followed by deep sequencing (ChIP-seq) revealed 21 binding regions, including previously characterized barR/Saci_2137 intergenic region. However, only one additional operon containing two glutamine synthase genes (Saci_2320 and Saci_2321) was found to be under activation of BarR. This operon is a common target of LyM and Sa-Lrp, which indicates a regulatory network between different Lrp-like regulators. In paper 2, we showed that a TetR family transcription repressor FadRSa regulates fatty acid metabolism in S. acidocaldarius. FadRSa rests in a gene cluster, Saci_1103-Saci_1126, that mainly contains lipid degradation and fatty acid metabolism genes. ChIP-seq revealed four binding sites within the gene cluster and RNA-seq further confirmed that the entire gene cluster is repressed by FadRSa. FadRSa binds DNA at a 16-base pair motif with dyad symmetry, and binding of medium- to long-chain acyl-CoA molecules resulted in dissociation of FadRSa from the DNA. Although FadRSa is similar to its bacterial counterparts functionally and structurally, fundamentally different ligand binding mode has been observed.

In paper 3, transcriptome data of S. solfataricus at four time points during growth, including early exponential phase, late exponential phase, early stationary phase and late stationary phase, has been studied and revealed a massive change in gene expressions during growth phase transition. 1067 out of a total of 2978 (35.8%) protein coding genes were identified as differentially expressed, which included 456 induced genes most of which were related to transposase, metabolism and stress response, 464 repressed genes most of them involved in translation, basic transcription, DNA replication, amino acids metabolism and defence mechanisms, and 147 genes with fluctuated profile including transporters, oxidation-reduction process related genes and few metabolic genes.

In summary, the studies of two metabolic related TFs in S. acidocaldarius, BarR and FadRSa, shed light on their function and regulatory mechanisms. In addition, the transcriptome data of S. solfataricus not only reveals genome-wide alteration of gene expression during growth phase transition, but also provide a rich source of information for further studies by the archaea research community.

Place, publisher, year, edition, pages
Stockholm: Department of Molecular Biosciences, The Wenner-Gren Institute, Stockholm University, 2018. p. 51
Keywords
Archaea, Sulfolobus, Transcription regulation, Lrp, TetR, BarR, ChIP-seq, RNA-seq, Transcriptome, growth phase transition
National Category
Natural Sciences
Research subject
Molecular Bioscience
Identifiers
urn:nbn:se:su:diva-153538 (URN)978-91-7797-189-4 (ISBN)978-91-7797-190-0 (ISBN)
Public defence
2018-04-27, Högbomsalen, Geovetenskapens Hus, Svante Arrhenius väg 12, Stockholm, 10:00 (English)
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Supervisors
Note

At the time of the doctoral defense, the following papers were unpublished and had a status as follows: Paper 2: Manuscript. Paper 3: Manuscript.

Available from: 2018-04-04 Created: 2018-03-09 Last updated: 2018-03-22Bibliographically approved

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