Illuminating the dark side of the genome

Jul 29, 2014
The Suv39h enzymes (Suv39h1/Suv39h2) are selectively enriched at the active retrotransposons, which make up around 2% of all repeats. Suv39h-mediated H3K9me3 represses these potentially dangerous elements and thereby contributes to the genome integrity in mouse stem cells. Credit: J. Faber/MPI-IE with Material from Wikipedia.

Almost 50 percent of our genome is made up of highly repetitive DNA, which makes it very difficult to be analysed. In fact, repeats are discarded in most genome-wide studies and thus, insights into this part of the genome remained limited. Scientists from the Max Planck Institute of Immunobiology and Epigenetics (MPI-IE) in Freiburg now succeeded in examining this dark side of the genome. Their analyses revealed that repeat-associated heterochromatin is essential to repress retrotransposons and thereby protects the genomic integrity of stem cells. This work opens the way for future genome-wide analyses of repetitive regions in the genome and is in line with newly emerging functions for heterochromatin.

Only 1 % of the human genome contains coding information, while the remaining 99 % harbour non-coding and repetitive DNA. DNA and its packaging proteins (histones) create a polymer called chromatin that also regulates gene expression. There are two major chromatin states: Euchromatin is open or accessible and thus, genes can be activated. In contrast, heterochromatin is closed or inaccessible and therfore, genes are repressed. Despite rapid advances in sequencing technologies, the repetitive content of the genome remained an enigma due to its redundancy, which interferes with standard protocols. However, understanding the chromatin organization and transcriptional regulation of such regions is important, as they contain many potentially harmful genetic elements called (retro)transposons. Transposons, or 'jumping genes' are mobile genetic elements that can multiply and insert at various positions in the DNA, which can lead to gene disruptions. Moreover, transcriptional de-regulation of retrotransposons is a hallmark of several human cancers.

A research team led by Prof. Dr. Thomas Jenuwein, director at the MPI-IE, now investigated these genome areas in mouse stem cells using heterochromatin factors. They conducted genome-wide mapping for the enzyme 'histone methyltransferase Suv39h', one of the most prominent enzymes involved in heterochromatin formation, and its catalytic product, methylation of the packaging protein histone H3 at lysine 9. Subsequent refined bioinformatic analyses allowed the identification of repeat-associated heterochromatin. "Developing new bioinformatic tools for the analysis of repetitive regions was the key to this study," says Jenuwein. " This was only possible due to the close interaction of our wet lab scientists with the bioinformatics unit of Thomas Manke at the MPI-IE."

The new approach showed that repeat-associated has an important function to safeguard the genomic integrity of embryonic mouse stem cells. The Suv39h enzyme mainly targets retrotransposons of the LINE and LTR family. Surprisingly, Suv39h specifically silences only intact, and therefore potentially active, elements, which barely make up 2% of all retrotransposons. Upon loss of Suv39h, only these elements become transcriptionally upregulated. "Initially, we were surprised to see that such a small fraction of the repetitive responds to epigenetic regulation" explains co-first author Dr. Inti De La Rosa-Velazquez. "However, it makes sense to only regulate the potentially harmful elements. Now, we are very interested to dissect the molecular mechanism that allows the Suv39h enzymes to identify active retrotransposons."

In addition to stem cells, the researchers also investigated repetitive regions in more differentiated cells. In neural precursor cells or fibroblasts, retrotransposons lose histone methylation and instead accumulate DNA methylation, another epigenetic mechanism for gene silencing. This suggests that Suv39h-dependent repression is specific for stem cells. "Previous studies had shown that DNA methylation is the primary silencing mechanism for retrotransposons in differentiated cells", elaborates Jenuwein. "However, in which show reduced levels of DNA methylation, chromatin-based mechanisms were expected to safeguard retrotransposon repression. With our work on the Suv39h enzymes we have now identified such a pathway."

Explore further: Viral 'parasites' may play a key role in the maintenance of cell pluripotency

add to favorites email to friend print save as pdf

Related Stories

Making and breaking heterochromatin

Sep 25, 2012

To fit the two-meter long DNA molecule into a cell nucleus that is only a few thousandths of a millimetre in size, long sections of the DNA must be strongly compacted. Epigenetic marks maintain these sections, ...

Silence of the genes

Jul 22, 2011

A molecular mechanism by which gene silencing is regulated at the genome-wide level in plants has been uncovered by a research team led by Motoaki Seki of the RIKEN Plant Science Center, Yokohama, Japan. ...

The role of H3K9 in bringing order to the nucleus

Aug 31, 2012

(—Scientists from the Friedrich Miescher Institute for Biomedical Research have elucidated the histone modifications that lead to the sequestration of silent genes at the nuclear periphery. In ...

Preventing the spread of repression

Aug 08, 2013

Scientists at the Friedrich Miescher Institute for Biomedical Research have identified a novel and unexpected regulatory activity of RNA at the edge of inactive chromosomal regions. In their publication in Nature Structural an ...

Recommended for you

Researchers capture picture of microRNA in action

10 hours ago

Biologists at The Scripps Research Institute (TSRI) have described the atomic-level workings of "microRNA" molecules, which control the expression of genes in all animals and plants.

Blocking a fork in the road to DNA replication

12 hours ago

A team of Whitehead Institute scientists has discovered the surprising manner in which an enigmatic protein known as SUUR acts to control gene copy number during DNA replication. It's a finding that could shed new light on ...

Cell division, minus the cells

14 hours ago

( —The process of cell division is central to life. The last stage, when two daughter cells split from each other, has fascinated scientists since the dawn of cell biology in the Victorian era. ...

A new method simplifies the analysis of RNA structure

15 hours ago

To understand the function of an RNA molecule, similar to the better-known DNA and vital for cell metabolism, we need to know its three-dimensional structure. Unfortunately, establishing the shape of an RNA ...

User comments : 0

Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.