Abstract
Transposons impart dynamism to the genomes they inhabit and their movements frequently rewire the control of nearby genes. Occasionally, their proteins are domesticated when they evolve a new function. SETMAR is a protein methylase with a sequence-specific DNA binding domain. It began to evolve about 50 million years ago when an Hsmar1 transposon integrated downstream of a SET-domain methylase gene. Here we show that the DNA-binding domain of the transposase targets the enzyme to transposon-end remnants and that this is capable of regulating gene expression, dependent on the methylase activity. When SETMAR was modestly overexpressed in human cells, almost 1500 genes changed expression by more than 2-fold (65% up- and 35% down-regulated). These genes were enriched for the KEGG Pathways in Cancer and include several transcription factors important for development and differentiation. Expression of a similar level of a methylase-deficient SETMAR changed the expression of many fewer genes, 77% of which were down-regulated with no significant enrichment of KEGG Pathways. Our data is consistent with a model in which SETMAR is part of an anthropoid primate-specific regulatory network centered on the subset of genes containing a transposon end.
Highlights
Transposable elements (TEs) are almost ubiquitous and their transposases are the most abundant genes in nature [1]
We set out to test the hypothesis that the primary function of SETMAR is mediated by the targeting of the protein to a subset of the 7000 Hsmar1 remnants dispersed throughout the human genome (Figure 1A)
In this study we tested the hypothesis that the DNA-binding domain and methylase domain of SETMAR are both important for its biological activity
Summary
Transposable elements (TEs) are almost ubiquitous and their transposases are the most abundant genes in nature [1]. It is clear that TEs are an important source of genetic novelty [3] They promote the emergence of new gene regulatory networks by dispersing transcription factor binding site in the genome and they give rise to new microRNAs and long intergenic non-coding RNAs [4,5,6,7,8,9]. One of the best examples is V(D)J recombination in the vertebrate immune system [10] In this case, the RAG1 recombinase and the recombination signal sequences preserve almost all of the respective functions of the ancestral transposase and its cognate binding sites in the transposon ends (inverted terminal repeats, ITRs). The precise functions of the other ∼50 domesticated transposase proteins in the human genome remain unknown [14]
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