Researchers uncover the key cellular control mechanisms that regulate gene expression and prevent the activation of ancient viral sequences hidden within our genomes, shedding light on a crucial process for survival and development.
Cracking the Code of the Genome’s Dark Matter
The two of us have huge genomes: 3 billion genetic building blocks, provide or take a few hundred million. But this inundation of data also presents a question: how do cells regulate which genes to express (and when, and where)?
And that answer lies in the form of epigenetic signatures, which serve as a kind of ‘highlight’ tool for the genome. These markings, akin to marginal notes in a book, can tell cells whether to read or pass over each section of the genome. The activity of ancient viral sequences that linger in our genome is tightly controlled, and a group led by researchers at the European Molecular Biology Laboratory (EMBL) in Heidelberg, Germany has now uncovered a critical piece of this control.
Silencing the Viral Echoes
Screening studies by the researchers zeroed in on a protein called H3. 3, a histone — a molecule that helps spool DNA in the cell. They found that cargo on two distinct positions on the “tail” of H3, which is situated toward the finish of a long chain of amino acids known as the N-terminus, impelled infection causing recombination. Proteins at the K9 and K27 positions are often post-translationally modified by ubiquitination. These changes are considered as epigenetic ‘tags’ and help the cell to recognize which genes should be active.
The scientists experimentally mutated these sites and created a version of H3. 3 were unsubstitutable in silico. This allowed them to see firsthand what would happen if those critical mechanisms of control were gone.
These alterations had profound effects, however: the researchers found that mutating these sites disrupted cell differentiation, growth and survival; moreover, they drove widespread activation of genes across the genome – launching inappropriate expression from genes normally kept silent in stem cells including certain immune-related genes. This hinted at the idea that part of what these sites normally do is to keep these genes in a ‘repressed’, or silenced, mode — which would also help stem cells stay as stem cells.
Conclusion
The implications of these results are more profound in the context of gene regulation and the relationship between gene expression and development or disease. The researchers identify cellular control mechanisms that silence ancient viral sequences, illuminating a key process that maintains the balance between gene expression and cellular identity. This understanding could change our thinking in developmental biology and open new avenues of cancer research, and inform much work in neuroscience where the correct regulation of gene activity is at a premium.
