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Dimerization and Transactivation Domains as Candidates for Functional Modulation and Diversity of Sox9 - PubMed

  • ️Fri Jan 01 2016

Dimerization and Transactivation Domains as Candidates for Functional Modulation and Diversity of Sox9

Marcos Tadeu Geraldo et al. PLoS One. 2016.

Abstract

Sox9 plays an important role in a large variety of developmental pathways in vertebrates. It is composed of three domains: high-mobility group box (HMG box), dimerization (DIM) and transactivation (TAD). One of the main processes for regulation and variability of the pathways involving Sox9 is the self-gene expression regulation of Sox9. However, the subsequent roles of the Sox9 domains can also generate regulatory modulations. Studies have shown that TADs can bind to different types of proteins and its function seems to be influenced by DIM. Therefore, we hypothesized that both domains are directly associated and can be responsible for the functional variability of Sox9. We applied a method based on a broad phylogenetic context, using sequences of the HMG box domain, to ensure the homology of all the Sox9 copies used herein. The data obtained included 4,921 sequences relative to 657 metazoan species. Based on coevolutionary and selective pressure analyses of the Sox9 sequences, we observed coevolutions involving DIM and TADs. These data, along with the experimental data from literature, indicate a functional relationship between these domains. Moreover, DIM and TADs may be responsible for the functional plasticity of Sox9 because they are more tolerant for molecular changes (higher Ka/Ks ratio than the HMG box domain). This tolerance could allow a differential regulation of target genes or promote novel targets during transcriptional activation. In conclusion, we suggest that DIM and TADs functional association may regulate differentially the target genes or even promote novel targets during transcription activation mediated by Sox9 paralogs, contributing to the subfunctionalization of Sox9a and Sox9b in teleosts.

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Conflict of interest statement

Competing Interests: The authors have declared that no competing interests exist.

Figures

Fig 1
Fig 1. Evolutionary relationships among the Sox9 vertebrate sequences.

(A) Phylogeny of the Sox9 multiple sequence alignment using the maximum likelihood method from the PhyML program. The aLRT (SH-like) values of branch support are shown. The corresponding clades for Sox9 (blue), Sox9a (green) and Sox9b (orange) are indicated. The database entries (accession numbers from GenBank or Ensembl) are shown with their corresponding annotations in the database in parenthesis. The single asterisks (*) indicates the divergences between our results and the gene annotation in the corresponding database entry, whereas the double asterisks (**) indicates the sequence obtained from the genome walking technique. The scale bar below the phylogenetic tree indicates the average number of nucleotides substitutions per site. (B) Dendogram of the synteny analysis, based on the closest genetic markers: the clades corresponding to Sox9 (blue), Sox9a (green) and Sox9b (orange) were obtained from the hierarchical manhattan clustering method, implemented in the R software.

Fig 2
Fig 2. Network of coevolutions in the Sox9 proteins.

(A) The coevolutions are shown using D. rerio Sox9a, M. albus Sox9b and H. sapiens Sox9 as the reference sequences. The graph nodes indicate the amino acid with its corresponding position number in the reference sequence. The edges (lines) connect the pair of coevolving amino acids inferred from the CAPS program. Each amino acid is colored based on its localization in the corresponding Sox9 domain: DIM (purple), HMG box (light blue), K2 (orange), PQA (dark cyan) and PQS (red). The range (begin-end) of each domain is also depicted in the scheme. The sign for truncated regions (//) is used for fitting the figure dimensions. (B) The Sox9 multiple protein sequence alignment is indicated. The color of each domain follows the description aforementioned. Upper green bars evidence high conserved sites.

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Grants and funding

This study was supported by São Paulo Research Foundation (FAPESP) [grant numbers 2009/05234-4; 2010/13143-6] and National Counsel of Technological and Scientific Development (CNPq) [grant number 475147/2010-3]. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.