The Developmental Control of Transposable Elements and the Evolution of Higher Species

Transposable elements (TEs) account for at least 50% of the human genome. They constitute essential motors of evolution through their ability to modify genomic architecture, mutate genes and regulate gene expression. Accordingly, TEs are subject to tight epigenetic control during the earliest phases of embryonic development via histone and DNA methylation. Key to this process is recognition by sequence-specific RNA- and protein-based repressors. Collectively, these mediators are responsible for silencing a very broad range of TEs in an evolutionarily dynamic fashion. As a consequence, mobile elements and their controllers exert a marked influence on transcriptional networks in embryonic stem cells and a variety of adult tissues. The emerging picture is not that of a simple arms race but rather of a massive and sophisticated enterprise of TE domestication for the evolutionary benefit of the host.

KRAB zinc-finger proteins contribute to the evolution of gene regulatory networks

Pierre-Yves Joseph Laurent Helleboid, Michaël Imbeault, Didier Trono

The human genome encodes some 350 Kruppel-associated box (KRAB) domain-containing zinc-finger proteins (KZFPs), the products of a rapidly evolving gene family that has been traced back to early tetrapods(1,2). The function of most KZFPs is unknown, but a few have been demonstrated to repress transposable elements in embryonic stem (ES) cells by recruiting the transcriptional regulator TRIM28 and associated mediators of histone H3 Lys9 trimethylation (H3K9me3)-dependent heterochromatin formation and DNA methylation(3-9). Depletion of TRIM28 in human or mouse ES cells triggers the upregulation of a broad range of transposable elements(4,10,11), and recent data based on a few specific examples have pointed to an arms race between hosts and transposable elements as an important driver of KZFP gene selection(5). Here, to obtain a global view of this phenomenon, we combined phylogenetic and genomic studies to investigate the evolutionary emergence of KZFP genes in vertebrates and to identify their targets in the human genome. First, we unexpectedly reassigned the root of the family to a common ancestor of coelacanths and tetrapods. Second, although we confirmed that the majority of KZFPs bind transposable elements and pinpoint cases of ongoing co-evolution, we found that most of their transposable element targets have lost all transposition potential. Third, by examining the interplay between human KZFPs and other transcriptional modulators, we obtained evidence that KZFPs exploit evolutionarily conserved fragments of transposable elements as regulatory platforms long after the arms race against these genetic invaders has ended. Together, our results demonstrate that KZFPs partner with transposable elements to build a largely species-restricted layer of epigenetic regulation.

Nature Publishing Group2017

Transposable Elements, Polydactyl Proteins, and the Genesis of Human-Specific Transcription Networks

Didier Trono

Transposable elements (TEs) may account for up to two-thirds of the human genome, and as genomic threats they are subjected to epigenetic control mechanisms engaged from the earliest stages of embryonic development. We previously determined that an important component of this process is the sequence-specific recognition of TEs by KRAB (Krüppel-associated box)-containing zinc-finger proteins (KRAB-ZFPs), a large family of tetrapod-restricted transcription factors that act by recruiting inducers of heterochromatin formation and DNA methylation. We further showed that KRAB-ZFPs and their cofactor KAP1 exert a marked influence on the transcription dynamics of embryonic stem cells via their docking of repressor complexes at TE-contained regulatory sequences. It is generally held that, beyond this early embryonic period, TEs become permanently silenced, and that the evolutionary selection of KRAB-ZFPs and other TE controllers is the result of a simple evolutionary arms race between the host and these genetics invaders. Here, I discuss recent evidence that invalidates this dual assumption and instead suggests that KRAB-ZFPs are the instruments of a massive enterprise of TE domestication, whereby transposon-based regulatory sequences and their cellular ligands establish species-specific transcription regulation networks that influence multiple aspects of human development and physiology.

2016

KRAB zinc finger protein-mediated control of transposon-embedded regulatory sequences from human germline to early embryos

Alexandra Iouranova

Transposable elements (TEs), also called jumping genes, are genetic elements capable of changing their position within the genome of their host. They make up large fractions of genomes, including 45% of human DNA content, according to current estimates. Some of these elements are of retroviral origin and are known as endogenous retroviruses (ERVs). Long terminal repeats (LTRs) of ERVs, like other TEs, influence host gene expression in various ways. They can for example create new promoters, enhancers or imprinted regions upon integration. As ERVs derive from a germline infection in the common ancestor of a species, they are often restricted to a particular evolutionary clade. While rewiring by TEs can harm a host genome, some of the features of TE invasions can increase host fitness and appear to be universally exploited by various organisms. For instance, TE insertions happen faster than protein-coding genes evolve. They can therefore be coopted for a species-specific evolutionary remodeling of transcriptional networks. Specifically, the LTR12/ERV9 TE family has colonized primate genomes over the past 30 million years and has been widely reported to contribute regulatory elements to the human genome. In this work, we set out to establish the features that made this family successful, and to assess the prevalence of LTR12-derived regulatory elements in early development. We observe the hominoid-restricted LTR12C subfamily to be a driver of transcription in both gametogenesis and early embryogenesis. LTR12C loci have rewired genes involved in ciliogenesis and flagellogenesis that are critical for male fertility. Relatedly, they also present unusual behavior during the epigenetic reprogramming characteristic of these periods by resisting genome-wide demethylation in primordial germ cell (PGC) development. To identify the determinants of the epigenetic status of LTR12C elements that made them attractive for cooption, we turn to KRAB zinc finger proteins (KZFPs). TEs appear to be prominent targets of this large family of epigenetic repressors. Through functional studies, we determine ZNF676 is a regulator of LTR12C, with its targets resisting genome-wide demethylation. This resistance possibly pre-marks them for zygotic rather than maternal expression. We show that ZNF676 levels influence the expression of some cilium-related genes and are able to disrupt ciliogenesis. We conclude this KZFP likely coevolved with its target ERVs, which carried its binding sites into the vicinity of multiple genes, including those important for male fertility. KZFPs can therefore become regulators of genes with a common function along with the transposable elements they target. More generally, in our study of TEs expressed in human embryonic development, we find the expression of some TE families to be a hallmark of a particular development stage, an indicator of the current chromatin state. These markers provide a criterion that can be used to assess the similarity of embryonic development models to real embryos. Transcription of some marker TEs anticorrelates with that of their putative KZFP regulators, implying proper KZFP expression to be important to properly recapitulate embryonic development. Our results provide insight into the TE- and KZFP-mediated rewiring of transcriptional networks related to the germline and early development, and suggest that the improper expression of a KZFP can have consequences ranging up to infertility.

EPFL2021

KRAB zinc finger protein-mediated control of transposon-embedded regulatory sequences from human germline to early embryos

Alexandra Iouranova

EPFL2021