Researchers at GMI – Gregor Mendel Institute of Molecular Plant Biology of the Austrian Academy of Sciences – are discovering an engineering mechanism by which Arabidopsis protects the integrity of its genome. The paper is published in the journal Natural Cell Biology.
Is it possible for a single gene product to silence unwanted genetic elements? Is such a strong effect visible in the regulation of Transposable Elements (TEs), or genomic parasites? If so, how does this gene product alone control transpositions? New research by Frédéric Berger’s group at GMI provides answers to these questions and dissects a mechanism of gene silencing that has long remained shrouded in mystery.
Although jump transposons promote genomic variation at an evolutionary scale, their effects on an individual organism are very detrimental. If left unregulated, they could lead to gender instability and various diseases. In the Arabidopsis model plant, loss of function of a single gene product identified 30 years ago, Decreased DNA Methylation I (DDM1), has been shown to result in extensive and uncontrollable transmission events. DDM1 is a chromatin remodeler that helps keep DNA tightly packaged to silence TEs, but the underlying mechanism, how DDM1 silences TEs, is still unknown.
Caught before they jump!
The team around GMI group leader Frédéric Berger, with co-authors Akihisa Osakabe and Bhagyshree Jamge, describes the molecular mechanism of action of DDM1. They show that DDM1 targets TEs by binding H2A.W, a variant of the histone H2A, one of the building blocks that line DNA to form the condensed and tightly packaged heterochromatin. The team shows that H2A.W deposition of DDM1 on DNA-rich regions with TEs is not only necessary, but also sufficient to restructure the chromatin and silence the TEs. Importantly, the team demonstrates that this mechanism dominates many other known TE silencing mechanisms in Arabidopsis and that the effect of DDM1 is specific for skipping genes with intact transposition potential, i.e. possibly mobile TEs. “Transposers integrate the genome and thus share chromatin with the host. They can be viewed as enemies hiding in houses. What distinguishes these houses from those that house protein-coding genes? – The material used to build these houses is different : it sanctifies transpositions that they cannot go out and multiply, ”says Frédéric Berger. The silencing mechanism described does not affect fragments of jumping genes that have lost their ability to transmit independently, nor does it affect gene coding proteins. Frédéric Berger does not hesitate to describe the mechanism somewhat humorously: “Basically the strategy is: to sanctify your enemy into building blocks of special material and send him to hell!”.
Shipped to hell packed by DHL
The association with hell comes from “hells,” the name of the human ortholog of Arabidopsis DDM1. The researchers are proposing a new class of chromatin restructurers, grouping DDM1 and Hells along with their mouse orthologist Lsh, which they call “DHL”. DHL chromatin remodelers show conserved binding sites for the histone variants. In addition, all three restructurers were associated with genomic instability and disease in their respective organisms, in case mutations cause their loss of function.
DHL remodelers control transposition dynamics
DDM1 is the key factor in “camouflaging” TEs away from the transcription machinery by using special “building blocks” that prevent their recognition. Asked about the wider impact of this new mechanism, Frédéric Berger claims: “DDM1 orthologs in mammals deposit the H2A.W orthologous variant macroH2A, which has been implicated in various human syndromes and cancers. Better knowledge of the mechanism of action of this class of histone binding proteins will advance our understanding of gene dynamics with effects on medicine and development ”.
Engineered silencing devices in yeast
Frédéric Berger, who received funding from the “1000 Ideen” grant for high-risk research from the Austrian Science Fund (FWF), is already exploring emerging features of these histone variants and chromatin remodelers and realizing new silent pathways in yeast based on the Arabidopsis H2A.W and DDM1.
Osakabe, Jamge et al., “The chromatin remodeling DDM1 prevents transposer motility by deposition of histone variant H2A.W”, Natural Cell Biology, 2021. DOI: https: /
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