Abstract
The NET (for NocA, Nlz, Elbow, TLP-1) protein family is a group of conserved zinc finger proteins linked to embryonic development and recently associated with breast cancer. The members of this family act as transcriptional repressors interacting with both class I histone deacetylases and Groucho/TLE co-repressors. In Drosophila, the NET family members Elbow and NocA are vital for the development of tracheae, eyes, wings and legs, whereas in vertebrates ZNF703 and ZNF503 are important for the development of the nervous system, eyes and limbs. Despite the relevance of this protein family in embryogenesis and cancer, many aspects of its origin and evolution remain unknown. Here, we show that NET family members are present and expressed in multiple metazoan lineages, from cnidarians to vertebrates. We identified several protein domains conserved in all metazoan species or in specific taxonomic groups. Our phylogenetic analysis suggests that the NET family emerged in the last common ancestor of cnidarians and bilaterians and that several rounds of independent events of gene duplication occurred throughout evolution. Overall, we provide novel data on the expression and evolutionary history of the NET family that can be relevant to understanding its biological role in both normal conditions and disease.
Highlights
The NET protein family is a group of conserved zinc finger proteins linked to embryonic development and more recently to cancer[2,3,4]
The search for proteins belonging to the NET family in different databases (Ensembl, NCBI and Joint Genome Institute (JGI)) allowed us to recover 165 protein sequences from different metazoan lineages ranging from cnidarians to vertebrates (Supplementary Table S1)
We have observed that several fish species have two Znf[703] (Nlz1) and two Znf[503] (Nlz2) proteins (Supplementary Table S1), most likely due to the fish-specific whole genome duplication (WGD) event[27]
Summary
The NET protein family is a group of conserved zinc finger proteins linked to embryonic development (reviewed in ref. 1) and more recently to cancer[2,3,4]. Vertebrates have two NET family members, the ZNF703 ( known as Nlz1) and ZNF503 ( known as Nlz2) paralogous proteins, which were first described in zebrafish[11,12]. NET members during embryonic development in humans remain uncharacterized, we have previously shown that ZNF703 is expressed ubiquitously in human adult tissues[21]. It was recently shown that ZNF703 can repress TGFBR2 (transforming growth factor βreceptor II) and E-cadherin expression[2,26] as well as human TGF-βand TCF/β-catenin-mediated transcription[21,26]. We sought to determine the expression of NET members in the diversity of metazoan lineages, refine the NET protein-conserved domains and reconstruct the phylogeny and gene arrangement around NET family genes in metazoans
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