The vertebrate RCAN gene family: novel insights into evolution, structure and regulation

PLoS One. 2014 Jan 20;9(1):e85539. doi: 10.1371/journal.pone.0085539. eCollection 2014.

Abstract

Recently there has been much interest in the Regulators of Calcineurin (RCAN) proteins which are important endogenous modulators of the calcineurin-NFATc signalling pathway. They have been shown to have a crucial role in cellular programmes such as the immune response, muscle fibre remodelling and memory, but also in pathological processes such as cardiac hypertrophy and neurodegenerative diseases. In vertebrates, the RCAN family form a functional subfamily of three members RCAN1, RCAN2 and RCAN3 whereas only one RCAN is present in the rest of Eukarya. In addition, RCAN genes have been shown to collocate with RUNX and CLIC genes in ACD clusters (ACD21, ACD6 and ACD1). How the RCAN genes and their clustering in ACDs evolved is still unknown. After analysing RCAN gene family evolution using bioinformatic tools, we propose that the three RCAN vertebrate genes within the ACD clusters, which evolved from single copy genes present in invertebrates and lower eukaryotes, are the result of two rounds of whole genome duplication, followed by a segmental duplication. This evolutionary scenario involves the loss or gain of some RCAN genes during evolution. In addition, we have analysed RCAN gene structure and identified the existence of several characteristic features that can be involved in RCAN evolution and gene expression regulation. These included: several transposable elements, CpG islands in the 5' region of the genes, the existence of antisense transcripts (NAT) associated with the three human genes, and considerable evidence for bidirectional promoters that regulate RCAN gene expression. Furthermore, we show that the CpG island associated with the RCAN3 gene promoter is unmethylated and transcriptionally active. All these results provide timely new insights into the molecular mechanisms underlying RCAN function and a more in depth knowledge of this gene family whose members are obvious candidates for the development of future therapies.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Biological Evolution*
  • Chromosome Mapping
  • DNA-Binding Proteins
  • Gene Expression Regulation*
  • Genome
  • Humans
  • Intracellular Signaling Peptides and Proteins / genetics*
  • Intracellular Signaling Peptides and Proteins / metabolism
  • Muscle Proteins / genetics*
  • Muscle Proteins / metabolism
  • Vertebrates / genetics

Substances

  • DNA-Binding Proteins
  • Intracellular Signaling Peptides and Proteins
  • Muscle Proteins
  • RCAN1 protein, human

Grant support

The research was supported by Ministerio de Ciencia e Innovación grant SAF2009-08216 and Generalitat Catalunya grant 2009SGR1490. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. ESC was supported by SAF009-08216 and Mutua Madrileña, DF was supported by the Juan de la Cierva subprogramme (Ministerio de Economía y Competitividad), and AAI was a recipient of a FI fellowship from Generalitat de Catalunya.