Hominoid-Specific Transposable Elements and KZFPs Facilitate Human Embryonic Genome Activation and Control Transcription in Naive Human ESCs

Abstract

Summary Expansion of transposable elements (TEs) coincides with evolutionary shifts in gene expression. TEs frequently harbor binding sites for transcriptional regulators, thus enabling coordinated genome-wide activation of species- and context-specific gene expression programs, but such regulation must be balanced against their genotoxic potential. Here, we show that Krüppel-associated box (KRAB)-containing zinc finger proteins (KZFPs) control the timely and pleiotropic activation of TE-derived transcriptional cis regulators during early embryogenesis. Evolutionarily recent SVA, HERVK, and HERVH TE subgroups contribute significantly to chromatin opening during human embryonic genome activation and are KLF-stimulated enhancers in naive human embryonic stem cells (hESCs). KZFPs of corresponding evolutionary ages are simultaneously induced and repress the transcriptional activity of these TEs. Finally, the same KZFP-controlled TE-based enhancers later serve as developmental and tissue-specific enhancers. Thus, by controlling the transcriptional impact of TEs during embryogenesis, KZFPs facilitate their genome-wide incorporation into transcriptional networks, thereby contributing to human genome regulation.

The interactome of KRAB zinc finger proteins reveals the evolutionary history of their functional diversification

“…Our data and published studies (Porsch-Ö zcürü mez et al, 2001;Shin et al, 2011;Chauhan et al, 2013) further suggest that, during the course of these events, some KZFPs evolved other functions that supplemented, modulated, or replaced transcriptional repression, a functional modification that went parallel to a shift of their genomic enrichment from active TEs to sequences likely derived therefrom but no longer recognizable as such, and that the positive selection of these new functions allowed their KZFP mediators to escape the evolutionary flushing of family members that had become obsolete because only involved in repressing now defunct TEs. This model is supported by additional evolutionary evidence such as (i) the highly dynamic and species-specific populations of KZFPs present in the genomes of all tetrapods ; (ii) signs of an evolutionary arms race with TE sequences displaying escape mutations following the emergence of their controlling KZFP (Thomas & Schneider, 2011;Jacobs et al, 2014;Imbeault et al, 2017); (iii) the spreading of canonical transcription factor binding sites in vertebrate genomes via the expansion of lineage-restricted TEs (Bourque et al, 2008;Schmid & Bucher, 2010;Schmidt et al, 2012;Sundaram et al, 2014;Grow et al, 2015;Chuong et al, 2016); and (iv) the prominent role played by KZFPs to promote the genomewide exaptation of these TEsderived regulatory sequences through the taming of their transcriptional impact during early embryogenesis (Pontis et al, 2019).…”

Endogenous retroviruses are a source of enhancers with oncogenic potential in acute myeloid leukaemia

“…LTR12C elements, for example, were previously shown to frequently act as alternative gene promoters in different cell types, including hepatocellular carcinoma (Hashimoto et al, 2015) and cell lines treated with DNMT and HDAC inhibitors (Brocks et al, 2017). In contrast, LTR5_Hs (HERV-K) elements appear to mainly act as distal enhancer elements in embryonic carcinoma cells and embryonic stem cells (Fuentes et al, 2018;Pontis et al, 2019). We therefore aimed to establish whether A-DARs could act as promoters and/or enhancers in AML.…”

“…LTRs frequently recombine, leaving the majority of ERV elements as intact solitary LTRs with potential gene regulatory activity (Belshaw et al, 2007;Thomas et al, 2018). In line with this notion, genome-wide assays have documented that numerous LTR sequences carry hallmarks of active regulatory elements (Chuong et al, 2016;Fuentes et al, 2018;Jacques et al, 2013;Kunarso et al, 2010;Lynch et al, 2011;Pontis et al, 2019;Sundaram et al, 2014). In a few instances, loss-of-function experiments have provided compelling evidence of LTR co-option for host gene regulation and cellular function in hematopoiesis (Pi et al, 2010), innate immunity (Chuong et al, 2016), pregnancy (Ferreira et al, 2016) and fertility (Flemr et al, 2013).…”

Impacts of genomic networks governed by human-specific regulatory sequences and genetic loci harboring fixed human-specific neuro-regulatory single nucleotide mutations on phenotypic traits of Modern Humans

“…Importantly, human-specific GRNs utilized in these analyses were defined employing vastly different experimental, analytical, and computational approaches that were applied within the broad range of experimental settings (Glinsky, 2019). Specifically, the interrogated human-specific GRNs include the following data sets: i) Great Apes' whole-genome sequencing-guided identification of human-specific insertions and deletions (Kronenberg et al, 2018); ii) genome-wide analysis of retrotransposon's transcriptome in postmortem samples of human dorsolateral prefrontal cortex (Guffanti et al, 2018); iii) shRNA-mediated silencing of LTR7/HERVH retrovirus-derived long non-coding RNAs in hESC (Wang et al, 2014); iv) single-cell expression profiling analyses of human preimplantation embryos ; v) network of genes associated with regulatory transposable elements (TE) operating in naïve and primed hESC (Theunissen et al, 2016;Pontis et al, 2019); vi) pluripotency-related network of genes manifesting concordant expression changes in human fetal brain and adult neocortex (Glinsky, 2017); vii) network of genes governing human neurogenesis in vivo (Nowakowski et al, 2017); viii) network of genes differentially expressed during human corticogenesis in vitro (van de Leemput et al, 2014). Thus, selected for these analyses human-specific GRNs appear to function in a developmentally and physiologically diverse spectrum of human cells that are biologically and anatomically certified by peer review) is the author/funder.…”