scholarly journals The promoter regions of intellectual disability-associated genes are uniquely enriched in LTR sequences of the MER41 primate-specific endogenous retrovirus: an evolutionary connection between immunity and cognition

2018 ◽  
Author(s):  
Serge Nataf ◽  
Juan Uriagereka ◽  
Antonio Benitez-Burraco
Keyword(s):  
Intellectual Disability ◽  
Protein Sequences ◽  
Autism Spectrum ◽  
Endogenous Retrovirus ◽  
Human Cognition ◽  
Human Endogenous Retrovirus ◽  
Signal Transducer ◽  
Long Terminal Repeats ◽  
Promoter Regions ◽  
Human Neurons

ABSTRACTSocial behavior and neuronal connectivity in rodents have been shown to be shaped by the prototypical T lymphocyte-derived pro-inflammatory cytokine Interferon-gamma (IFNγ). It has also been demonstrated that STAT1 (Signal Transducer And Activator Of Transcription 1), a transcription factor (TF) crucially involved in the IFNγ pathway, binds consensus sequences that, in humans, are located with a high frequency in the LTRs (Long Terminal Repeats) of the MER41 family of primate-specific HERVs (Human Endogenous Retrovirus). However, the putative role of an IFNγ/STAT1/MER41 pathway in human cognition and/or behavior is still poorly documented. Here, we present evidence that the promoter regions of intellectual disability-associated genes are uniquely enriched in LTR sequences of the MER41 HERVs. This observation is specific to MER41 among more than 130 HERVs examined. Moreover, we have not found such a significant enrichment in the promoter regions of genes that associate with autism spectrum disorder (ASD) or schizophrenia. Interestingly, ID-associated genes exhibit promoter-localized MER41 LTRs that harbor TF binding sites (TFBSs) for not only STAT1 but also other immune TFs such as, in particular, NFKB1 (Nuclear Factor Kappa B Subunit 1) and STAT3 (Signal Transducer And Activator Of Transcription 3). Moreover, IL-6 (Interleukin 6) rather than IFNγ, is identified as the main candidate cytokine regulating such an immune/MER41/cognition pathway. Of note, functionally-relevant differences between humans and chimpanzees are observed regarding the 3 main components of this pathway: i) the protein sequences of immunes TFs binding MER41 LTRs, ii) the insertion sites of MER41 LTRs in the promoter regions of ID-associated genes and iii) the protein sequences of the targeted ID-associated genes. Finally, a survey of the human proteome has allowed us to map a protein-protein network which links the identified immune/MER41/cognition pathway to FOXP2 (Forkhead Box P2), a key TF involved in the emergence of human speech. Together, these results suggest that the stepped self-domestication of MER41 in the genomes of primates could have been a driver of cognitive evolution. Our data further indicate that non-inherited forms of ID might result from alterations of the immune/MER41/cognition pathway induced notably by the untimely or quantitatively inappropriate exposure of human neurons to IL-6.

scholarly journals Human Endogenous Retrovirus HERV-K14 Families: Status, Variants, Evolution, and Mobilization of Other Cellular Sequences

2005 ◽  
Vol 79 (5) ◽  
pp. 2941-2949 ◽  
Author(s):  
Aline Flockerzi ◽  
Stefan Burkhardt ◽  
Werner Schempp ◽  
Eckart Meese ◽  
Jens Mayer
Keyword(s):  
Human Genome ◽  
Germ Line ◽  
Endogenous Retrovirus ◽  
Endogenous Retroviruses ◽  
Human Endogenous Retrovirus ◽  
Long Terminal Repeats ◽  
Essential Information ◽  
Human Endogenous Retroviruses ◽  
Consensus Sequences

ABSTRACT The human genome harbors many distinct families of human endogenous retroviruses (HERVs) that stem from exogenous retroviruses that infected the germ line millions of years ago. Many HERV families remain to be investigated. We report in the present study the detailed characterization of the HERV-K14I and HERV-K14CI families as they are represented in the human genome. Most of the 68 HERV-K14I and 23 HERV-K14CI proviruses are severely mutated, frequently displaying uniform deletions of retroviral genes and long terminal repeats (LTRs). Both HERV families entered the germ line ∼39 million years ago, as evidenced by homologous sequences in hominoids and Old World primates and calculation of evolutionary ages based on a molecular clock. Proviruses of both families were formed during a brief period. A majority of HERV-K14CI proviruses on the Y chromosome mimic a higher evolutionary age, showing that LTR-LTR divergence data can indicate false ages. Fully translatable consensus sequences encoding major retroviral proteins were generated. Most HERV-K14I loci lack an env gene and are structurally reminiscent of LTR retrotransposons. A minority of HERV-K14I variants display an env gene. HERV-K14I proviruses are associated with three distinct LTR families, while HERV-K14CI is associated with a single LTR family. Hybrid proviruses consisting of HERV-K14I and HERV-W sequences that appear to have produced provirus progeny in the genome were detected. Several HERV-K14I proviruses harbor TRPC6 mRNA portions, exemplifying mobilization of cellular transcripts by HERVs. Our analysis contributes essential information on two more HERV families and on the biology of HERV sequences in general.

scholarly journals Structure and Phylogenetic Analysis of an Endogenous Retrovirus Inserted into the Human Growth Factor Gene Pleiotrophin

1998 ◽  
Vol 72 (7) ◽  
pp. 6065-6072 ◽  
Author(s):  
Anke M. Schulte ◽  
Anton Wellstein
Keyword(s):  
Rhesus Monkeys ◽  
Human Growth ◽  
Endogenous Retrovirus ◽  
Primer Binding Site ◽  
Human Endogenous Retrovirus ◽  
Long Terminal Repeats ◽  
Reading Frame ◽  
Growth Factor Gene ◽  
Trna Primer ◽  
Type C

ABSTRACT A human endogenous retrovirus-like element (HERV), flanked by long terminal repeats of 502 and 495 nucleotides is inserted into the human pleiotrophin (PTN) gene upstream of the open reading frame. Based on its Glu-tRNA primer binding site specificity and the location within the PTN gene, we named this element HERV-E.PTN. HERV-E.PTN appears to be a recombined viral element based on its high homology (70 to 86%) in distinct areas to members of two distantly related HERV type C families, HERV-E and retrovirus-like element I (RTVL-I). Furthermore, its pseudogene region is organized from 5′ to 3′ into gag-,pol-, env-, pol-,env-similar sequences. Interestingly, full-length and partial HERV-E.PTN-homologous sequences were found in the human X chromosome, the human hereditary haemochromatosis region, and the BRCA1 pseudogene. Finally, Southern analyses indicate that the HERV-E.PTN element is present in the PTN gene of humans, chimpanzees, and gorillas but not of rhesus monkeys, suggesting that genomic insertion occurred after the separation of monkeys and apes about 25 million years ago.

scholarly journals CpG Methylation Directly Regulates Transcriptional Activity of the Human Endogenous Retrovirus Family HERV-K(HML-2)

2005 ◽  
Vol 79 (2) ◽  
pp. 876-883 ◽  
Author(s):  
Laurence Lavie ◽  
Milena Kitova ◽  
Esther Maldener ◽  
Eckart Meese ◽  
Jens Mayer
Keyword(s):  
Cell Line ◽  
Transcriptional Activity ◽  
Significant Proportion ◽  
Endogenous Retrovirus ◽  
Cpg Methylation ◽  
Endogenous Retroviruses ◽  
Human Endogenous Retrovirus ◽  
Long Terminal Repeats ◽  
Cpg Sites

ABSTRACT A significant proportion of the human genome consists of stably inherited retroviral sequences. Most human endogenous retroviruses (HERVs) became defective over time. The HERV-K(HML-2) family is exceptional because of its coding capacity and the possible involvement in germ cell tumor (GCT) development. HERV-K(HML-2) transcription is strongly upregulated in GCTs. However, regulation of HERV-K(HML-2) transcription remains poorly understood. We investigated in detail the role of CpG methylation on the transcriptional activity of HERV-K(HML-2) long terminal repeats (LTRs). We find that CpG sites in various HERV-K(HML-2) proviral 5′ LTRs are methylated at different levels in the cell line Tera-1. Methylation levels correlate with previously observed transcriptional activities of these proviruses. CpG-mediated silencing of HERV-K(HML-2) LTRs is further corroborated by transcriptional inactivity of in vitro-methylated 5′ LTR reporter plasmids. However, CpG methylation levels do not solely regulate HERV-K(HML-2) 5′ LTR activity, as evidenced by different LTR activities in the cell line T47D. A significant number of mutated CpG sites in evolutionary old HERV-K(HML-2) 5′ LTRs suggests that CpG methylation had already silenced HERV-K(HML-2) proviruses millions of years ago. Direct silencing of HERV-K(HML-2) expression by CpG methylation enlightens upregulated HERV-K(HML-2) expression in usually hypomethylated GCT tissue.

Some morphological, growth, and genomic properties of human cells chronically infected with porcine endogenous retrovirus (PERV)

Genome ◽  
2003 ◽  
Vol 46 (5) ◽  
pp. 858-869 ◽  
Author(s):  
Ruhul H Kuddus ◽  
Chandrashekhar R Gandhi ◽  
Khaja K Rehman ◽  
Fengli Guo ◽  
Simon C Watkins ◽  
...  
Keyword(s):  
Rflp Analysis ◽  
Endogenous Retrovirus ◽  
Human Cells ◽  
Band Pattern ◽  
Human Endogenous Retrovirus ◽  
Long Term Effects ◽  
Long Terminal Repeats ◽  
Hek 293 ◽  
Porcine Endogenous Retrovirus ◽  
Infected Cells

A major concern in using porcine organs for transplantation is the potential of transmission of porcine endogenous retrovirus (PERV). To investigate the long-term effects of PERV infection on human cells, human embryonic kidney cell line HEK-293 infected with PERV PK-15 was maintained for up to 72 passages and samples were harvested at intervals for use in morphological, growth, and genomic analyses. Morphology, DNA content/cell, and doubling time of uninfected and infected cells were similar. Restriction fragment length polymorphism (RFLP) analysis of PCR-amplified nearly full-length PERV genome showed no alterations in band pattern. RFLP analysis of the long terminal repeats (LTR) showed some changes in band pattern, but not in length. Southern blot analysis of genomic DNA of infected cells indicated random integration of PERV without structural alterations in proviral genome. Semi-quantitative PCR demonstrated a gradual increase of proviral load in the infected cells. Sequence analysis of the LTR region of PERV from infected cells indicated a relatively low rate (6.0 × 10–4/bp or about 2 × 10–6/bp/generation) of mutation. There were also indications of recombination of PERV strains A and B. Finally, PERV infection had no effect on transcription of human endogenous retrovirus-K (HERV-K) genes. Together, no significant effect attributable to PERV infection was evident on chronically PERV-infected HEK-293 cells.Key words: porcine endogenous retrovirus (PERV), human endogenous retrovirus-K (HERV-K), xenotransplantation, zoonosis.

scholarly journals Primate-restricted KRAB zinc finger proteins and target retrotransposons control gene expression in human neurons

2019 ◽  
Author(s):  
Priscilla Turelli ◽  
Christopher Playfoot ◽  
Dephine Grun ◽  
Charlène Raclot ◽  
Julien Pontis ◽  
...  
Keyword(s):  
Zinc Finger ◽  
Embryonic Stem ◽  
Zinc Finger Proteins ◽  
Endogenous Retrovirus ◽  
Adult Brain ◽  
Human Endogenous Retrovirus ◽  
Regulatory Sequences ◽  
Human Neurons ◽  
And Function ◽  
Transcription Networks

AbstractIn the first days of embryogenesis, transposable element-embedded regulatory sequences (TEeRS) are silenced by Kruppel-associated box (KRAB)-zinc finger proteins (KZFPs). Many TEeRS are subsequently coopted in transcription networks, but how KZFPs influence this process is largely unknown. We identify ZNF417 and ZNF587 as primate-specific KZFPs repressing HERVK (human endogenous retrovirus K) and SVA (SINE-VNTR-Alu) integrants in human embryonic stem cells (ESC). Expressed in specific regions of the human developing and adult brain, ZNF417/587 keep controlling TEeRS in ESC-derived neurons and brain organoids, secondarily influencing the differentiation and neurotransmission profile of neurons and preventing the induction of neurotoxic retroviral proteins and an interferon-like response. Thus, evolutionarily recent KZFPs and their TE targets partner up to influence human neuronal differentiation and physiology.One Sentence SummaryYoung transposable elements and their protein controllers team up to regulate the differentiation and function of human neurons.

scholarly journals Human Endogenous Retrovirus K Rec Forms a Regulatory Loop with MITF that Opposes the Progression of Melanoma to an Invasive Stage

Viruses ◽  
2020 ◽  
Vol 12 (11) ◽  
pp. 1303 ◽  
Author(s):  
Manvendra Singh ◽  
Huiqiang Cai ◽  
Mario Bunse ◽  
Cédric Feschotte ◽  
Zsuzsanna Izsvák
Keyword(s):  
Target Genes ◽  
Endogenous Retrovirus ◽  
Human Endogenous Retrovirus ◽  
Mrna Levels ◽  
Long Terminal Repeats ◽  
Normal Tissues ◽  
E Box ◽  
Regulatory Loop ◽  
Species Specific

The HML2 subfamily of HERV-K (henceforth HERV-K) represents the most recently endogenized retrovirus in the human genome. While the products of certain HERV-K genomic copies are expressed in normal tissues, they are upregulated in several pathological conditions, including various tumors. It remains unclear whether HERV-K(HML2)-encoded products overexpressed in cancer contribute to disease progression or are merely by-products of tumorigenesis. Here, we focus on the regulatory activities of the Long Terminal Repeats (LTR5_Hs) of HERV-K and the potential role of the HERV-K-encoded Rec in melanoma. Our regulatory genomics analysis of LTR5_Hs loci indicates that Melanocyte Inducing Transcription Factor (MITF) (also known as binds to a canonical E-box motif (CA(C/T)GTG) within these elements in proliferative type of melanoma, and that depletion of MITF results in reduced HERV-K expression. In turn, experimentally depleting Rec in a proliferative melanoma cell line leads to lower mRNA levels of MITF and its predicted target genes. Furthermore, Rec knockdown leads to an upregulation of epithelial-to-mesenchymal associated genes and an enhanced invasion phenotype of proliferative melanoma cells. Together these results suggest the existence of a regulatory loop between MITF and Rec that may modulate the transition from proliferative to invasive stages of melanoma. Because HERV-K(HML2) elements are restricted to hominoid primates, these findings might explain certain species-specific features of melanoma progression and point to some limitations of animal models in melanoma studies.

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