New insights into ‘DNA parasites’ and genomic stability

A study led by newly recruited faculty Simon Elsässer at Karolinska Institutet/SciLifeLab shows that a specialized histone protein, one of the abundant molecules responsible for packaging our DNA in the cell nucleus, maintains genomic stability by silencing 'parasitic' DNA-elements. The study was published in Nature.

Simon Elsässer joined Karolinska Institutet and the SciLifeLab in the beginning of 2015, from the MRC Laboratory of Molecular Biology, Cambridge, UK. In his research, he focuses on applying new synthetic and chemical biology methods to understand chromatin structure and function. Publishing in Nature, together with colleagues at the Rockefeller University in New York, USA he has now elucidated the mechanism of how certain DNA elements in mouse cells are silenced. These 'parasitic' DNA elements called transposons can jump and multiply within a host genome and have played an active role in animal evolution, facilitating genetic variation and adaptation. But their activity represents a threat to the host genome and thus they are almost always actively repressed, or silenced, by various proteins and regulatory RNAs produced by the host genome.

Simon Elsässer’s team has found a new factor that is used to mark specific DNA elements that should be silenced. It is a protein called histone H3.3, a variant of the canonical histone H3. Histones are proteins that wrap our DNA like strings on beads and facilitate packing of DNA 10 000 fold to fit in the cell nucleus. Through this packaging mechanism, researchers think that histone proteins are the key to regulating access to the genetic information by making different parts of the DNA accessible to factors that express the gene, so-called epigenetic regulation.

“Histone proteins carry a large number of distinct hemical modifications or ‘marks’, providing a verbose epigenetic language,” says Simon Elsässer. “As a field, we have only started to appreciate the intricate complexity of this histone code. It has been appreciated in the last decade that, just like errors in the genetic language itself, failure to maintain the epigenetic information can cause human disease, such as developmental disorders or cancer".

Exceptionally strong signal

H3.3 has been intensely studied in other processes, but until now no one has looked at transposable elements. Unexpectedly, the current study shows that a large fraction of H3.3 occupies transposable elements in the mouse embryonic stem cells and that it is required to permanently silence the underlying DNA elements. The combination of H3.3 and a known silencing mark – histone H3 lysine 9 trimethylation (which in no other instance are found together) – provides an exceptionally strong signal to the cell to 'not read from this genomic region'.

When Simon Elsässer’s team deleted all H3.3 genes, they found that certain previously silenced transposable elements were reactivated and continued to multiply in the genome; the result is the appearance of new genetic alleles and chromosomal abnormalities, both are familiar early events in the formation of tumors.

The researchers think that, while different types of transposable elements are prevalent in humans, the same mechanism may be in action in human cells. Over the last few years a number of cancer types have been found to harbor frequent and recurrent mutations in the histone variant H3.3. The study has been funded by grants from the Rockefeller University Fund, the Tri-Institutional Stem Cell Initiative, and the Cambridge University Herchel Smith Fund.

• Read more about this research on the website of SciLifeLab
• View a press release from Rockefeller University

Publication

Histone H3.3 is required for endogenous retroviral element silencing in embryonic stem cells
Simon J. Elsässer, Kyung-Min Noh, Nichole Diaz, C. David Allis, Laura A. Banaszynski
Nature, online 4 May 2015, doi: 10.1038/nature14345