How cells hack their own genes
DNA in organisms from yeast to humans encodes the genes that make it possible to live and reproduce. But these beneficial genes make up only small portions of the DNA—in humans less than 5%. More than two-thirds of our genome instead is composed of selfish genes and their evolutionary remnants. Selfish genes only care about their own replication and are therefore often dubbed genetic parasites. Scattered throughout the genomes of plants, fungi, and animals, they can jump from one genomic location to another. Although they can be important for generating diversity in the genome, they can also cause mutations leading to reduced fitness or even sterility. Just as bacteria use CRISPR/Cas systems to identify and cleave viruses invading their DNA, eukaryotic cells have developed various strategies to protect the genome and silence the selfish genetic parasites. Small regulatory RNAs govern many of these genome-defense mechanisms and have also yielded major biotechnological innovations.
Solving an evolutionary “chicken and egg” dilemma
One important pathway that maintains the genomic integrity of animals is the piRNA pathway. This system is active in germ cells and utilizes small snippets of RNA—so called piRNAs—which fit like mirror images onto the transcripts of selfish sequences and thereby initiate silencing with their associated Argonaute proteins. The Brennecke lab at IMBA has been rigorously exploring this RNA-based self-defense mechanism in fruit flies by combining genetics with cutting-edge next generation sequencing technologies. This revealed that piRNAs originate from genomic regions that contain collections of the selfish elements. But how can piRNAs be generated from the very regions that they silence? In their current publication, Brennecke’s lab not only solves this enigma but also describes a surprising new mechanism for gene-expression within heterochromatin, a state of DNA that normally is programmed to suppress transcription.
Moonshiner: There is always a way around
The newly discovered pathway is centered on a protein called Moonshiner. Moonshiner is related to basal transcription factors, which facilitate transcription of DNA. It also interacts with Rhino, a protein bound to heterochromatin at the selfish genes. Rhino recruits Moonshiner to the heterochromatic region, and Moonshiner initiates assembly of the basal transcription complex, the so-called RNA polymerase II pre-initiation complex, that catalyze transcription. As a result, gene expression is activated in an otherwise silent region via a code that is embedded in chromatin marks rather than DNA sequence. The findings show that piRNAs are transcribed by bending the classical rules of gene activation. “The pathway, that is active at piRNA clusters – where the piRNAs are born – literally hacks the gene machinery by combining two different systems, gene activation with gene silencing, just like furniture can be repurposed by IKEA hacking,” illustrates Peter Andersen, Postdoc at IMBA and first author of the paper. The Moonshiner pathway thus reveals how cells can utilize heterochromatin for transcription. “Cells have developed strategies to bypass conventional gene expression pathways. Our findings are not only shining new light on the arms race between cellular genes and selfish genetic elements but they also allow us to study the different steps in gene expression in new ways,” says Julius Brennecke, IMBA group leader and last author.
'A heterochromatin-dependent transcription machinery drives piRNA expression', Andersen at al., Nature; DOI: 10.1038/nature23482
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