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Systematic perturbation of retroviral LTRs reveals widespread long-range effects on human gene regulation [ChIP-seq]

ABSTRACT: Recent work suggests extensive adaptation of transposable elements (TEs) for host gene regulation. However, high numbers of integrations typical of TEs, coupled with sequence divergence within families, have made systematic interrogation of the regulatory contributions of TEs challenging. Here, we employ CARGO, our recent method for CRISPR gRNA multiplexing, to facilitate targeting of LTR5HS, a higher primate-specific class of HERVK (HML-2) LTRs that is active during early development and present in ~700 copies throughout the human genome. We combine CARGO with CRISPR activation or interference to, respectively, induce or silence LTR5HS en masse, and demonstrate that this system robustly targets the vast majority of LTR5HS insertions. Remarkably, activation/silencing of LTR5HS is associated with reciprocal up- and down-regulation of hundreds of human genes. These effects require presence of retroviral sequences, but occur over long genomic distances, consistent with a pervasive function of LTR5HS elements as early embryonic enhancers in higher primates.

ORGANISM(S): Homo sapiens

PROVIDER: GSE111331 | GEO | 2018/08/16

REPOSITORIES: GEO

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Systematic perturbation of retroviral LTRs reveals widespread long-range effects on human gene regulation [RNA-seq]

Project description:Recent work suggests extensive adaptation of transposable elements (TEs) for host gene regulation. However, high numbers of integrations typical of TEs, coupled with sequence divergence within families, have made systematic interrogation of the regulatory contributions of TEs challenging. Here, we employ CARGO, our recent method for CRISPR gRNA multiplexing, to facilitate targeting of LTR5HS, a higher primate-specific class of HERVK (HML-2) LTRs that is active during early development and present in ~700 copies throughout the human genome. We combine CARGO with CRISPR activation or interference to, respectively, induce or silence LTR5HS en masse, and demonstrate that this system robustly targets the vast majority of LTR5HS insertions. Remarkably, activation/silencing of LTR5HS is associated with reciprocal up- and down-regulation of hundreds of human genes. These effects require presence of retroviral sequences, but occur over long genomic distances, consistent with a pervasive function of LTR5HS elements as early embryonic enhancers in higher primates.

2018-08-16 | GSE111332 | GEO

Systematic perturbation of retroviral LTRs reveals widespread long-range effects on human gene regulation [histone marks]

2018-12-19 | GSE124128 | GEO

HERVK HML-2 Target Enrichment Pilot

Project description:HERVK HML-2 Target Enrichment pilot experiment

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RNA-seq of HERVK-CRIPRi IPS and iN cells

Project description:dCas9KRAB and gRNA targeting HERVK TEs were used to repress the TEs in stem cells (hiPS) and in differentiated induced neurons (iN). As control, dCas9KRAB alone without gRNA was used.

2020-01-24 | GSE144151 | GEO

DNA bisulfite sequencing of Invader 4 LTRs in Drosophila

Project description:It has been claimed previously that loss of (cytosine-5) DNA methylation in Dnmt2 mutant embryos affected the establishment of silent chromatin at Invader4 LTRs (Phalke et al., 2009). The inability of Dnmt2 mutants to control TE expression after heat shock (GSE40432) raised the possibility that DNA methylation could be required for control of Invader 4 during the heat shock response. We used DNA bisulfite sequencing at Inv4 LTRs that were previously suggested to be methylated (Phalke et al., 2009).

2017-07-28 | GSE101967 | GEO

Hominid-specific transposable elements and KRAB-ZFPs facilitate human embryonic genome activation and transcription in naïve hESCs [ATAC-seq]

Project description:Transposable elements (TEs) are key to the evolutionary turnover of regulatory sequences. How they can play such an essential role in spite of their genotoxic potential is unknown. Here, we demonstrate that KRABcontaining zinc finger proteins control the timely and pleiotropic engagement of TE-derived cis-regulators of transcription. We first observed that evolutionary recent TEs of the SVA, HERVK and HERVH subgroups are major contributors to chromatin opening during human embryonic genome activation and act as KLF-stimulated enhancers in naïve embryonic stem cells. We then found that KZFPs of corresponding evolutionary ages are simultaneously induced and repress the transcriptional activity of these TEs. We finally determined that the same KZFP-controlled TE-based enhancers later serve as developmental and tissue-specific regulators of gene expression. Thus, by taming the transcriptional impact of TEs during early embryogenesis, KZFPs allow for their genome-wide incorporation into transcriptional networks, thereby contributing to the species-specificity of human genome regulation.

2019-04-30 | GSE130418 | GEO

Hominid-specific transposable elements and KRAB-ZFPs facilitate human embryonic genome activation and transcription in naïve hESCs [ChIP-seq]

2019-04-30 | GSE130417 | GEO

Hominid-specific transposable elements and KRAB-ZFPs facilitate human embryonic genome activation and transcription in naïve hESCs [RNA-seq]

2019-04-30 | GSE130416 | GEO

Retrotransposon-based profiling of mammalian epigenomes: DNA methylation of IAP LTRs in embryonic stem, somatic and cancer cells

Project description:In this study, we analyzed the DNA methylation levels of 4799 IAP LTRs in three murine cell types: AB2.2 ES cells, somatic cells and a neuroblastoma cell line Neuro2A. According to the results, half of the IAP LTR retrotransposons show constant methylation patterns between the three cell types whereas the remaining half display variable levels of methylation. About half of the variably methylated IAP LTRs tend to be hypomethylated in ES cells, and nearly all of this group are hypomethylated in Neuro2A cells. Interestingly, the observed hypomethylation in both cell types occur in a non-uniform, locus-specific manner and to various degrees of severity, with some of them being easily detectible by COBRA. Overall, this study demonstrates the feasibility of HT-TREBS to study alterations in DNA methylation at retrotransposons in a locus-specific manner in multiple cell types and further suggests the potential utility of this technique in developing epigenetic biomarkers for tracking disease progression. HT-TREBS has been used with the Ion Torrent PGM platform to analyze the DNA methylation of 4799 IAP LTRs in a locus-specific manner in 3 cell types: somatic cells (previously submitted under GEO Accession GSE49222), AB2.2 ES cells and Neuro2A cells

2015-06-15 | E-GEOD-60007 | biostudies-arrayexpress

Active endogenous retroviral elements in human pluripotent stem cells are functional in regulating host gene expression

Project description:Human endogenous retroviruses were also called LTR elements which can be bound by transcription factors and marked by different histone modifications. In previous studies, LTR had been considered harmful to genome stability, but recently individual LTR or certain subclasses of LTRs such as LTR7/HERVH and LTR5/HERVK families had been identified as functional elements which had acted as a cis-regulatory element, constructed topological domains and contributed to immunity. However, there were still many LTR elements with unknown functions, and the biological significance of LTR for the host was poorly understood. Overall, our study has not only provided a comprehensive regulatory map of LTRs in human ESCs, but also explored the regulatory models of MER57E3 and LTR5_Hs on host genes.

2022-04-01 | GSE186430 | GEO

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