Although jumping genes have been known to jumpstart beneficial evolutionary changes, they also pose an immediate threat. They can destabilize the genome with deleterious mutations. Fortunately, jumping genes are usually kept in place, thanks to epigenetic control of the genome. In particular, the histones around which DNA is spooled can help suppress jumping genes, provided the right histones are able to attract the right chemical markers.
New details of how histones can help silence potentially errant retrotransposons have emerged from studies with mouse stem cells. Stem cells provide a good testing ground because they are known to have chromatin landscapes more plastic than those of differentiated cells. In differentiated cells, parts of the genome are permanently shut down, and these parts may include retrotransposons, making it difficult to distinguish between general, differentiation-related silencing and jumping-gene-specific silencing.
Scientists have known that mouse stem cells keep most of the genome accessible, while keeping the lid on retrotransposons by tagging them with chemical markers containing three methyl groups on histone H3. Following up on these findings, researchers at Rockefeller University have done work that suggests that a particular histone variant, H3.3, is necessary for the placement of these suppressive “trimethyl” marks. H3.3 varies from its regular counterpart H3 by only few amino acids. Because it is present throughout the animal kingdom, however, scientists have suspected for some time that H3.3 has a specific biological role.
“By taking away proteins responsible for placing H3.3 into chromatin, or eliminating H3.3 completely, we confirmed that trimethylation depends on H3.3,” said Laura Banaszynski, Ph.D., a former Rockefeller researcher who is currently an assistant professor at the University of Texas Southwestern Medical Center.
“Furthermore, retrotransposons became more active in cells without H3.3, and in these cells, we saw chromosomal abnormalities. It may be that by silencing retrotransposons, H3.3 prevents these abnormalities; however we cannot eliminate the possibility that loss of H3.3 results in this genomic instability for other reasons,” added Simon Elsasser, Ph.D., another former Rockefeller researcher. (He is now an assistant professor at the Karolinska Institute in Sweden.)
Both Dr. Banaszynski and Dr. Elsasser worked in the laboratory of C. David Allis, Ph.D., who offered these comments: “They say that good things come in small packages. Nowhere is this more true than with histone variants. This study found the variant H3.3, which differs only slightly from the standard H3 histones, helps prevent certain genetic elements, which are remnants left behind by ancient viral infections, from moving about within the genome. This discovery is an important addition to our still-evolving knowledge of how epigenetics works at the molecular level.”
The scientists presented their work May 4 in Nature, in an article entitled, “Histone H3.3 is required for endogenous retroviral element silencing in embryonic stem cells.” Although the types of retrotransposons evaluated in the current study are not active in humans, it's likely that human stem cells do use H3.3 to keep other varieties of jumping genes in place, noted Dr. Banaszynski.
“We demonstrate a hierarchy for deposition of H3.3, favoring DAXX–ATRX-mediated chromatin assembly at ERVs over transcription-associated deposition,” the authors of the study wrote. “We propose a model in which H3.3-containing chromatin facilitates the recruitment of KAP1 to ERVs, which in turn recruits DAXX–ATRX for the maintenance of H3.3 chromatin, thus creating a positive feedback or propagation loop.”
The authors concluded that their findings solidify an emerging understanding of the importance of the histone variant H3.3 in the establishment of silenced chromatin states and in maintenance of genome stability. They also speculated that their research has implications beyond epigenetics. According to Dr. Banaszynski, “This study also hints at a fascinating question in biology: How do cells balance the potential evolutionary benefit of mobile elements, such as retrotransposons, with the competing need to silence them so as to maintain the genome?”