The life cycle of endogenous retroviruses (ERVs), also called long terminal repeat (LTR) retrotransposons, begins with transcription by RNA polymerase II followed by reverse transcription and ...re-integration into the host genome. While most ERVs are relics of ancient integration events, “young” proviruses competent for retrotransposition—found in many mammals, but not humans—represent an ongoing threat to host fitness. As a consequence, several restriction pathways have evolved to suppress their activity at both transcriptional and post-transcriptional stages of the viral life cycle. Nevertheless, accumulating evidence has revealed that LTR sequences derived from distantly related ERVs have been exapted as regulatory sequences for many host genes in a wide range of cell types throughout mammalian evolution. Here, we focus on emerging themes from recent studies cataloging the diversity of ERV LTRs acting as important transcriptional regulatory elements in mammals and explore the molecular features that likely account for LTR exaptation in developmental and tissue-specific gene regulation.
Solitary long terminal repeats (LTRs) have been frequently domesticated into gene regulatory elements in mammals. Here, Thompson et al. evaluate the features of LTRs that account for the prevalence of this phenomenon and highlight recent studies providing insight into the molecular mechanisms that influence the exaptation of LTRs.
Kruppel-associated box zinc-finger proteins (KRAB-ZFPs) make up the largest family of transcription factors in humans. These proteins emerged in the last common ancestor of coelacanth and tetrapods, ...and have expanded and diversified in the mammalian lineage. Although their mechanism of transcriptional repression has been well studied for over a decade, the DNA-binding activities and the biological functions of these proteins have been largely unexplored. Recent large-scale ChIP-seq studies and loss-of-function experiments have revealed that KRAB-ZFPs play a major role in the recognition and transcriptional silencing of transposable elements (TEs), consistent with an ‘arms race model’ of KRAB-ZFP evolution against invading TEs. However, this model is insufficient to explain the evolution of many KRAB-ZFPs that appear to domesticate TEs for novel host functions. We highlight some of the mammalian regulatory innovations driven by specific KRAB-ZFPs, including genomic imprinting, meiotic recombination hotspot choice, and placental growth.
KRAB-ZFPs make up the largest class of DNA-binding transcription factors in mammals.
The KRAB-domain is a potent transcriptional repression domain that functions via recruitment of the TRIM28 corepressor which recruits heterochromatin-inducing machinery.
KRAB-ZFPs are rapidly evolving in mammals, primarily at the level of expansion of KRAB-ZFP gene clusters, likely in response to invading waves of TEs.
The majority of KRAB-ZFPs (∼2/3 in humans) interact with TEs via specific DNA-binding motifs.
Loss-of-function studies of KRAB-ZFP corepressors and individual KRAB-ZFPs demonstrate that KRAB-ZFPs transcriptionally repress target TEs and prevent latent enhancer/promoter activity within TEs from affecting nearby genes.
The continuous cycle of KRAB-ZFP evolution against TEs provides a driving force for new adaptations in mammals.
Nearly half of the human genome consists of endogenous retroelements (EREs) and their genetic remnants, a small fraction of which carry the potential to propagate in the host genome, posing a threat ...to genome integrity and cell organismal survival. The largest family of transcription factors in tetrapods, the Krüppel-associated box domain zinc finger proteins (KRAB-ZFPs), binds to specific EREs and represses their transcription. Since their first appearance over 400 million years ago, KRAB-ZFPs have undergone dramatic expansion and diversification in mammals, correlating with the invasions of new EREs. In this article we review our current understanding of the structure, function, and evolution of KRAB-ZFPs and discuss growing evidence that the arms race between KRAB-ZFPs and the EREs they target is a major driving force for the evolution of new traits in mammals, often accompanied by domestication of EREs themselves.
Transposable elements (TEs) promote genetic innovation but also threaten genome stability. Despite multiple layers of host defence, TEs actively shape mammalian-specific developmental processes, ...particularly during pre-implantation and extra-embryonic development and at the maternal-fetal interface. Here, we review how TEs influence mammalian genomes both directly by providing the raw material for genetic change and indirectly via co-evolving TE-binding Krüppel-associated box zinc finger proteins (KRAB-ZFPs). Throughout mammalian evolution, individual activities of ancient TEs were co-opted to enable invasive placentation that characterizes live-born mammals. By contrast, the widespread activity of evolutionarily young TEs may reflect an ongoing co-evolution that continues to impact mammalian development.
Transposable elements (TEs) are major components of eukaryotic genomes. However, the extent of their impact on genome evolution, function, and disease remain a matter of intense interrogation. The ...rise of genomics and large-scale functional assays has shed new light on the multi-faceted activities of TEs and implies that they should no longer be marginalized. Here, we introduce the fundamental properties of TEs and their complex interactions with their cellular environment, which are crucial to understanding their impact and manifold consequences for organismal biology. While we draw examples primarily from mammalian systems, the core concepts outlined here are relevant to a broad range of organisms.
Pregnancy and parturition are intricately regulated to ensure successful reproductive outcomes. However, the factors that control gestational length in humans and other anthropoid primates remain ...poorly defined. Here, we show the endogenous retroviral long terminal repeat transposon-like human element 1B (THE1B) selectively controls placental expression of corticotropin-releasing hormone (CRH) that, in turn, influences gestational length and birth timing. Placental expression of CRH and subsequently prolonged gestational length were found in two independent strains of transgenic mice carrying a 180-kb human bacterial artificial chromosome (BAC) DNA that contained the full length of CRH and extended flanking regions, including THE1B. Restricted deletion of THE1B silenced placental CRH expression and normalized birth timing in these transgenic lines. Furthermore, we revealed an interaction at the 5' insertion site of THE1B with distal-less homeobox 3 (DLX3), a transcription factor expressed in placenta. Together, these findings suggest that retroviral insertion of THE1B into the anthropoid primate genome may have initiated expression of CRH in placental syncytiotrophoblasts via DLX3 and that this placental CRH is sufficient to alter the timing of birth.
Transcriptional enhancers control cell-type–specific gene expression. Primed enhancers are marked by histone H3 lysine 4 (H3K4) mono/di-methylation (H3K4me1/2). Active enhancers are further marked by ...H3K27 acetylation (H3K27ac). Mixed-lineage leukemia 4 (MLL4/KMT2D) is a major enhancer H3K4me1/2 methyltransferase with functional redundancy with MLL3 (KMT2C). However, its role in cell fate maintenance and transition is poorly understood. Here, we show in mouse embryonic stem cells (ESCs) that MLL4 associates with, but is surprisingly dispensable for the maintenance of, active enhancers of cell-identity genes. As a result, MLL4 is dispensable for cell-identity gene expression and self-renewal in ESCs. In contrast, MLL4 is required for enhancer-binding of H3K27 acetyltransferase p300, enhancer activation, and induction of cell-identity genes during ESC differentiation. MLL4 protein, rather than MLL4-mediated H3K4 methylation, controls p300 recruitment to enhancers. We also show that, in somatic cells, MLL4 is dispensable for maintaining cell identity but essential for reprogramming into induced pluripotent stem cells. These results indicate that, although enhancer priming by MLL4 is dispensable for cell-identity maintenance, it controls cell fate transition by orchestrating p300-mediated enhancer activation.
TRIM28 is critical for the silencing of endogenous retroviruses (ERVs) in embryonic stem (ES) cells. Here, we reveal that an essential impact of this process is the protection of cellular gene ...expression in early embryos from perturbation by cis-acting activators contained within these retroelements. In TRIM28-depleted ES cells, repressive chromatin marks at ERVs are replaced by histone modifications typical of active enhancers, stimulating transcription of nearby cellular genes, notably those harboring bivalent promoters. Correspondingly, ERV-derived sequences can repress or enhance expression from an adjacent promoter in transgenic embryos depending on their TRIM28 sensitivity in ES cells. TRIM28-mediated control of ERVs is therefore crucial not just to prevent retrotransposition, but more broadly to safeguard the transcriptional dynamics of early embryos.
Embryonic stem (ES) cells are derived from blastocyst-stage embryos and are thought to be functionally equivalent to the inner cell mass, which lacks the ability to produce all extraembryonic ...tissues. Here we identify a rare transient cell population within mouse ES and induced pluripotent stem (iPS) cell cultures that expresses high levels of transcripts found in two-cell (2C) embryos in which the blastomeres are totipotent. We genetically tagged these 2C-like ES cells and show that they lack the inner cell mass pluripotency proteins Oct4 (also known as Pou5f1), Sox2 and Nanog, and have acquired the ability to contribute to both embryonic and extraembryonic tissues. We show that nearly all ES cells cycle in and out of this privileged state, which is partially controlled by histone-modifying enzymes. Transcriptome sequencing and bioinformatic analyses showed that many 2C transcripts are initiated from long terminal repeats derived from endogenous retroviruses, suggesting this foreign sequence has helped to drive cell-fate regulation in placental mammals.
Retroviral restriction is a complex phenomenon that, despite remarkable recent progress, is far from being well understood. In this Preview, we introduce an insightful study by Yang et al. that ...represents the first attempt to identify the global determinants of retroviral repression in pluripotent mammalian cells.
Retroviral restriction is a complex phenomenon that, despite remarkable recent progress, is far from being well understood. In this Preview, we introduce an insightful study by Yang et al. that represents the first attempt to identify the global determinants of retroviral repression in pluripotent mammalian cells.
PDF
