SRA AND EPIGENETICS

The SRA domain: a connection between DNA methylation and histone modifications within the epigenetic code? The Arabidopsis VIM family

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 Obiettivo del progetto (Objective)

'Heterochromatin in both mammals and plants is associated with methylation of cytosines within the DNA sequence. While DNA methylation is widespread in plants, fungi, and animals, it has been curiously lost in Saccharomyces cerevisiae, Schizosaccharomyces pombe, Caenorhabditis elegans, and Drosophila. However, the methylation system in Arabidopsis is very similar to that in mammals, showing that DNA methylation is highly conserved, and that Arabidopsis is an excellent model system to study it. DNA methylation is controlled by two different but equally important processes: establishment and maintenance. Two classes of DNA methyltransferases, DNMT3 and DNMT1, respectively, are responsible for them, and are conserved between mammals and plants. Maintenance DNA methyltransferases methylate hemi-methylated sites upon DNA replication, so that the methylated or unmethylated status is inherited on both of the two newly synthesized DNA molecules. Therefore, DNA methylation serves as a marker on genomic DNA that can persist over cell generations. Evidence suggests that methylation DNA is linked to the methylation status of the surrounding histones, a self-reinforcing feedback loop for the maintenance of DNA and histone methylation that may help to explain the remarkable stability of epigenetic silent states. A group of proteins with a methylated DNA-binding domain, the SRA domain, from both Arabidopsis and humans has been recently discovered with a potential role in recognizing hemymethylated DNA and interacting with chromatin remodeling factors. In this proposal, I plan to characterize the role of the Arabidopsis SRA-domain containing proteins family (VIM family) in DNA methylation control, and how this is related with histone acetylation and methylation in a way to regulate gene transcription and the epigenetic code.'

Introduzione (Teaser)

Nature stops some genes from being expressed with small chemical modifications of the DNA and associated proteins that can be inherited. Scientists have shown in part how this works in a plant model system.

Descrizione progetto (Article)

Chromatin in plants and animals is nothing but DNA folded with histone and non-histone proteins. Some portions of the chromatin (heterochromatin) contain genes whose expression is largely silenced through the addition of methyl groups to histone proteins (methylation). The association of heterochromatin with DNA methylation is possibly due to nearby histone methylation. In fact, DNA methylation can persist over generations, resulting in heritable changes in gene expression without changes in DNA sequence (epigenetics).

The plant Arabidopsis thaliana shares with mammals a recently discovered group of proteins that has a methylated DNA-binding domain that could play a role in DNA methylation. This suggests that A. thaliana could be a model system for DNA methylation in mammals. Original plans to study this system with the EU-funded project SRA AND EPIGENETICS were modified as another research team published their results about this system. Research focus was then applied to study of heterochromatin formation and its relationship to replication-related phenotype of atxr5/6 mutants.

Perseverance and creativity on the part of the project researchers enabled an in-depth analysis of controls on DNA replication (that also inhibits DNA re-replication or replication more than once during a cell cycle). Plants with mutations in specific histone methyltransferases, enzymes mediating transfer of methyl groups to histone proteins, demonstrated localised re-replication in heterochromatin.

Heterochromatin in both plants and animals is generally characterised by the methylation of both DNA and histones of type H3K9. In A. thaliana, the methylation sites are co-located and mutually self-stabilising. Research revealed that this plant can adapt to extracellular cues by regulating gene expression and histone deposition independently of DNA methylation. Work resulted in a patent application. Further studies on the relationship between histone H3K9 dimethylation (H3K9me2) and DNA methylation revealed a distinct and novel interplay between the two.

SRA AND EPIGENETICS contributed ground-breaking work to the field of epigenetics with important publications in internationally recognised scientific journals. Better understanding of the complex mechanisms of gene expression could eventually be important to disease characterisation and the development of novel therapies.