There has been an explosion in epigenetics research in the last few decades, focusing on DNA methylation, histone modifications/variants, and small RNAs. These epigenetic mechanisms underlie phenotypic changes that do not involve changes to the DNA sequence. Major breakthroughs in all these areas have been made by scientists at the Vienna BioCenter over the last 30 years.
One of the most surprising revelations from the landmark sequencing of the human genome was that the number of human genes is considerably lower than previously estimated, and is unexpectedly close to much simpler organisms. It is now clear that there is a further layer of complexity on top of the nucleotide sequence, which is described as the “epigenetic code”. Inside the cell’s nucleus, DNA is tightly packaged by histones and other proteins to form chromatin. Epigenetic modifications regulate the organization of chromatin, thus controlling when and how the genetic information can be accessed and used.
Scientists at the Vienna BioCenter have made seminal contributions to unravelling the nature of these epigenetic mechanisms, starting with Adrian Bird and Denise Barlow, who both focused on DNA methylation. Before joining the IMP in 1987, Adrian Bird had discovered so-called CpG islands, short regions rich in unmethylated CpG nucleotides. At the IMP, his lab was able to show that if these CpGs were methylated, they were protected from destruction by nucleases (Antequera et al., Cell 1989). At the same time, they identified a methyl-CpG binding protein involved in this protection (Meehan et al., Cell 1989). Denise Barlow came to the IMP in 1988 with an interest in genomic imprinting – a parental-specific, epigenetic gene silencing mechanism. Her group identified the first imprinted gene, mouse Igf2r (Barlow et al., Nature 1991) and subsequently showed a difference in DNA methylation between the maternally and paternally inherited Igf2r alleles (Stöger et al., Cell 1993). Significantly, they showed, in a collaboration with Erwin Wagner’s group at the IMP, that Igf2r is required to repress growth in development (Wang et al., Nature 1994), laying the groundwork for our current understanding of the function of imprinting. The work from these two groups provided the conceptual framework for understanding how and why DNA methylation acts to regulate gene expression.
When Thomas Jenuwein joined the IMP in 1993, he was searching for genes involved in epigenetic control in mammals. In 2000, his team identified an enzyme that selectively methylates lysine 9 of the histone H3 tail (H3K9) in vitro (Rea et al., Nature 2000). The discovery of site-specific histone methyltransferases was arguably one of the greatest breakthroughs in epigenetics, as it suggested a dynamic mechanism for the regulation of higher-order chromatin. It was helped greatly by the bioinformatics team of Frank Eisenhaber, who were able to predict the enzymatic activity by sequence analysis. The Jenuwein group subsequently made the seminal discovery that methylated H3K9 creates a binding site for HP1 proteins, heterochromatic adaptor molecules (Lachner et al., Nature 2001), demonstrating how the epigenetic mark can be ‘read’. Histone lysine methylation is now established as a central epigenetic modification in eukaryotic chromatin.
RNA-directed DNA Methylation
Since its founding in 2001, several groups at the GMI have focused on understanding the molecular mechanisms of epigenetics in plants and have made valuable contributions to the field. For example, the group of Antonius and Marjorie Matzke studied RNA-directed DNA methylation and identified several of the key proteins involved in this process, including the plant-specific RNA polymerase Pol IV (Kanno et al., Nature Genetics 2005).
Multiple groups from all four institutes are continuing the legacy started by the early pioneering work described above, ensuring that the Vienna BioCenter continues to be one of the most competitive centers for epigenetic research in the world.
Antequera F, Macleod D, Bird AP. Specific protection of methylated CpGs in mammalian nuclei. Cell 1989; 58:509–17.
Meehan RR, Lewis JD, McKay S, Kleiner EL, Bird AP. Identification of a mammalian protein that binds specifically to DNA containing methylated CpGs. Cell 1989 58:499–507.
Barlow DP, Stöger R, Herrmann BG, Saito K, Schweifer N. The mouse insulin-like growth factor type-2 receptor is imprinted and closely linked to the Tme locus. Nature 1991; 349:84–7.
Stöger R, Kubicka P, Liu CG, Kafri T, Razin A, Cedar H, Barlow DP. Maternal-specific methylation of the imprinted mouse Igf2r locus identifies the expressed locus as carrying the imprinting signal. Cell 1993; 73:61–71.
Rea S, Eisenhaber F, O'Carroll D, Strahl BD, Sun ZW, Schmid M, Opravil S, Mechtler K, Ponting CP, Allis CD, Jenuwein T. Regulation of chromatin structure by site-specific histone H3 methyltransferases. Nature 2000; 406:593–9.
Lachner M, O'Carroll D, Rea S, Mechtler K, Jenuwein T. Methylation of histone H3 lysine 9 creates a binding site for HP1 proteins. Nature 2001; 410:116–20.
Kanno T, Huettel B, Mette MF, Aufsatz W, Jaligot E, Daxinger L, Kreil DP, Matzke M, Matzke AJ. Atypical RNA polymerase subunits required for RNA-directed DNA methylation. Nature Genetics 2005; 37:761–5.