Sleeping with the enemy: Methylation-seeking retrotransposons across eukaryotic lineages
Dr Alex de Mendoza, ARC CoE Plant Energy Biology, The University of Western Australia, Australia
Genomic cytosine methylation is a major mechanism to transcriptionally silence transposable elements across eukaryotes. Therefore, transposable elements are expected to evolve mechanisms to evade methylation to remain active in the host genomes. However, the discovery of several retrotransposons that have hijacked DNA methylation through the acquisition of host genes challenges this expectation. In one case, three distinct retrotransposon classes have acquired cytosine DNA methyltransferases, most spectacularly in the genomes of Symbiodinium dinoflagellates, where hundreds to thousands of copies of these retrotransposons are likely to have influenced the host’s exceptional epigenomic landscape. In another case, a group of arthropod retrotransposons have acquired a functionally active Methyl-CpG Binding Domain. This domain guides the retrotransposon integration into methylated CpG-rich regions, which correspond to repetitive regions of the genome, thus likely decreasing the potentially harmful effects of new insertions. These illustrate the convoluted arms race between transposable elements and their host genomes. Both cases exemplify the delicate balance between expression and silencing that retrotransposons need to achieve in order to co-exist with their host. These serve as the first examples of how transposons can domesticate host genes central to epigenome regulation to their own advantage.
Transposable element control during germline development in Drosophila
Dr Felipe Karam Teixeira, University of Cambridge, UK
Impact of transposable elements on human gene regulation
Professor Joanna Wysocka, Stanford University, USA
Professor Wysocka’s team is interested in understanding how TEs can serve as a substrate for evolution of novel regulatory elements and functions in the primate lineage. During human pre-implantation development many TEs escape silencing and are transcribed at discreet stages, with most stage-specific regulation occurring at the class of LTR retrotransposons called endogenous retroviruses (ERVs), which are remnants of ancient retroviral infections. One such ERV class, called HERVK, retained coding potential and gives rise to the viral-like particles and proteins that are readily detected in human blastocysts and can influence innate immune response. The team discovered that HERVK LTR elements, called LTR5HS, function as ape-specific enhancers and regulate expression of nearly 300 human embryonic genes. A flip side to TEs serving as a playground for regulatory innovation is that mobile transposons are parasitic elements that pose an ongoing threat to the genome, and thus must be controlled by the host cell. The non-LTR retrotransposon LINE-1 (L1) is the only currently mobile autonomous TE in humans. In collaboration with the Bassik lab at Stanford, the team performed first genome-wide screen for regulators of L1 retrotransposition and identified ~150 human genes that either activate or repress L1 retrotransposition in human cells. Through this screen, the researchers discovered a novel mechanism dedicated to transcriptional silencing of evolutionarily young, full-length L1s immersed within transcriptionally permissive euchromatic environment, and showed that this silencing pathway also has a collateral effect on the host gene expression programs. Professor Wysocka will discuss these findings and talk about her team ongoing work.
The impact of transposable element invasions on the evolution of human neuronal gene expression
Dr Frank Jacobs, University of Amsterdam, the Netherlands
Approximately half of our genome consists of repetitive DNA sequences, mainly contained in transposable elements (TEs). TEs are retrovirus-derived DNA elements which copy-pasted themselves throughout our genome during vertebrate evolution. TE invasions have been a major driver of genome evolution but it remains elusive to which extent TEs have influenced how genes in the human genome are regulated. In previous work (Jacobs et al, 2014; Nature) Dr Jacobs’s team showed that KRAB zinc finger genes (KRAB-ZNFs) in our genome are in a continuous battle against invasions of TEs, revealing how the human genome is actually in a war against itself. His lab currently investigates how the ‘evolutionary arms race’ between TEs and KRAB-ZNFs has re-shaped gene-regulatory networks involved in human brain development. The team find that TE invasions provided our genome with novel gene-regulatory elements, adding an extra level of complexity to how, where and when neuronal genes in our genome are switched-on or -off. In addition, the researchers find that evolutionary changes in KRAB-ZNFs, provide them not only with the capacity to recognise and repress TEs, but also results in them recognising gene promoters. This suggests that both TEs and KRAB-ZNFs have added new primate-specific layers of gene regulation, repeatedly innovating gene expression networks throughout primate evolution. Consistent with this concept, the team presents one of these KRAB-ZNFs which initially evolved to repress TEs, but now has become a modulator of genes central to brain development. The researchers’ work shows that the impact of TE invasions lasts long after the TE has lost its capacity to replicate, which ironically, is largely due to our own genome’s defense mechanism to protect our genome from uncontrolled spreading of TEs.
Transposable elements in early mammalian development: do they burst?
Dr Maria-Elena Torres-Padilla, Institute of Epigenetics and Stem Cells, Helmholtz Centre Munich, Germany
In mammals, the terminally differentiated sperm and oocyte fuse to create a totipotent zygote upon fertilisation. The mechanisms underlying the epigenetic reprogramming towards totipotency that follows fertilisation are not fully understood, and the molecular features of totipotent cells remain scarce. Embryonic cells remain totipotent only for a restricted time window. During this time, embryonic cells are characterised by an atypical chromatin structure and reactivation of specific families of retrotransposons. Recently, it was reported that totipotent-like cells arise in ES cell cultures in vitro. Like in the embryo, these cells are characterised by the expression of MERVL LTR retrotransposons. To address how the expression of these elements is regulated during the transition between totipotent and pluripotent states, Dr Torres-Padilla’s team first examined histone modifications and chromatin structure in early mouse embryos. Remarkably, the researchers have found that specific features of embryonic chromatin are also present in totipotent-like cells in vitro. Based on this analysis, they have begun to decipher key molecular regulators of repetitive elements in the embryo, and how they contribute to shaping the regulatory programme of the newly formed embryo. The team’s results have identified candidate proteins that regulate chromatin function and expression of these elements and show that they can induce totipotency. The researchers are currently examining the role of these molecules in sustaining totipotency in the embryo. Dr Torres-Padilla will present her team’s latest results that reveal a new role for chromatin integrity in promoting epigenetic reprogramming and sustaining molecular features of totipotent cells.