Active endogenous retroviral elements in human pluripotent stem cells are functional in regulating host gene expression
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE186430 | GEO | 2022/04/01
REPOSITORIES: GEO
Similar Datasets
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.
2018-12-19 | GSE124128 | GEO
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
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 | GSE111331 | GEO
Project description:Covalent modifications of RNA and DNA both regulate numerous biological processes, including development and cancer. The most abundant modification of RNA is that of N6-methyladenosine(m6A), while in the case of DNA, the CpG cytosine methylation characterizes cis-regulatory elements for spatial-temporal gene regulation. Recent studies establish a role for RNA m6A in regulating chromatin through histone modifications. However, whether there is also interplay between RNA and DNA methylation remains unknown. We address this question by studying regulation of the primate-specific transposable element (TE), LTR7/HERV-H, that is specifically activated in human embryonic stem cells (hESCs). Exploiting a novel proteomic approach, we find the RNA m6A-reader, YTHDC2, binds to LTR/HERV-H chromatin through interaction with m6A-modified HERV-H transcripts. Significantly, YTHDC2 recruits DNA demethylase, TET1, to activate LTR7/HERV-H via 5-hydroxymethycytosine(5hmC)-mediated DNA methylation. Furthermore, the YTHDC2/LTR7-axis prevents neural conversion of hESCs. Our results establish previously unknown crosstalk between RNA m6A and DNA methylation and new mechanisms controlling TE activity and hESC fate. We focused on the regulation of the primate-specific TE family, LTR7/HERV-H that is specifically active in the pluripotent human embryonic stem cells (hESCs) then silenced in differentiated lineages. We develop CARGO-BioID, a CRISPR-based TE-centric proteomics approach, to identify the proteins associated with thousands of copies of endogenous LTR7/HERV-H loci and potentially regulate their activity in hESCs. We found YTHDC2 and TET1 interact with each other and subsequently regulate m6A level on HERVH transcripts and 5hmC level on HERV-H genomic loci, which is critical for LTR7/HERV-H activities.
2023-05-12 | GSE210865 | GEO
Project description:Covalent modifications of RNA and DNA both regulate numerous biological processes, including development and cancer. The most abundant modification of RNA is that of N6-methyladenosine(m6A), while in the case of DNA, the CpG cytosine methylation characterizes cis-regulatory elements for spatial-temporal gene regulation. Recent studies establish a role for RNA m6A in regulating chromatin through histone modifications. However, whether there is also interplay between RNA and DNA methylation remains unknown. We address this question by studying regulation of the primate-specific transposable element (TE), LTR7/HERV-H, that is specifically activated in human embryonic stem cells (hESCs). Exploiting a novel proteomic approach, we find the RNA m6A-reader, YTHDC2, binds to LTR/HERV-H chromatin through interaction with m6A-modified HERV-H transcripts. Significantly, YTHDC2 recruits DNA demethylase, TET1, to activate LTR7/HERV-H via 5-hydroxymethycytosine(5hmC)-mediated DNA methylation. Furthermore, the YTHDC2/LTR7-axis prevents neural conversion of hESCs. Our results establish previously unknown crosstalk between RNA m6A and DNA methylation and new mechanisms controlling TE activity and hESC fate. We focused on the regulation of the primate-specific TE family, LTR7/HERV-H that is specifically active in the pluripotent human embryonic stem cells (hESCs) then silenced in differentiated lineages. We develop CARGO-BioID, a CRISPR-based TE-centric proteomics approach, to identify the proteins associated with thousands of copies of endogenous LTR7/HERV-H loci and potentially regulate their activity in hESCs. We found YTHDC2 and TET1 interact with each other and subsequently regulate m6A level on HERVH transcripts and 5hmC level on HERV-H genomic loci, which is critical for LTR7/HERV-H activities.
2023-05-12 | GSE210864 | GEO
Project description:Covalent modifications of RNA and DNA both regulate numerous biological processes, including development and cancer. The most abundant modification of RNA is that of N6-methyladenosine(m6A), while in the case of DNA, the CpG cytosine methylation characterizes cis-regulatory elements for spatial-temporal gene regulation. Recent studies establish a role for RNA m6A in regulating chromatin through histone modifications. However, whether there is also interplay between RNA and DNA methylation remains unknown. We address this question by studying regulation of the primate-specific transposable element (TE), LTR7/HERV-H, that is specifically activated in human embryonic stem cells (hESCs). Exploiting a novel proteomic approach, we find the RNA m6A-reader, YTHDC2, binds to LTR/HERV-H chromatin through interaction with m6A-modified HERV-H transcripts. Significantly, YTHDC2 recruits DNA demethylase, TET1, to activate LTR7/HERV-H via 5-hydroxymethycytosine(5hmC)-mediated DNA methylation. Furthermore, the YTHDC2/LTR7-axis prevents neural conversion of hESCs. Our results establish previously unknown crosstalk between RNA m6A and DNA methylation and new mechanisms controlling TE activity and hESC fate. We focused on the regulation of the primate-specific TE family, LTR7/HERV-H that is specifically active in the pluripotent human embryonic stem cells (hESCs) then silenced in differentiated lineages. We develop CARGO-BioID, a CRISPR-based TE-centric proteomics approach, to identify the proteins associated with thousands of copies of endogenous LTR7/HERV-H loci and potentially regulate their activity in hESCs. We found YTHDC2 and TET1 interact with each other and subsequently regulate m6A level on HERVH transcripts and 5hmC level on HERV-H genomic loci, which is critical for LTR7/HERV-H activities.
2023-05-12 | GSE224670 | GEO
Project description:Covalent modifications of RNA and DNA both regulate numerous biological processes, including development and cancer. The most abundant modification of RNA is that of N6-methyladenosine(m6A), while in the case of DNA, the CpG cytosine methylation characterizes cis-regulatory elements for spatial-temporal gene regulation. Recent studies establish a role for RNA m6A in regulating chromatin through histone modifications. However, whether there is also interplay between RNA and DNA methylation remains unknown. We address this question by studying regulation of the primate-specific transposable element (TE), LTR7/HERV-H, that is specifically activated in human embryonic stem cells (hESCs). Exploiting a novel proteomic approach, we find the RNA m6A-reader, YTHDC2, binds to LTR/HERV-H chromatin through interaction with m6A-modified HERV-H transcripts. Significantly, YTHDC2 recruits DNA demethylase, TET1, to activate LTR7/HERV-H via 5-hydroxymethycytosine(5hmC)-mediated DNA methylation. Furthermore, the YTHDC2/LTR7-axis prevents neural conversion of hESCs. Our results establish previously unknown crosstalk between RNA m6A and DNA methylation and new mechanisms controlling TE activity and hESC fate. We focused on the regulation of the primate-specific TE family, LTR7/HERV-H that is specifically active in the pluripotent human embryonic stem cells (hESCs) then silenced in differentiated lineages. We develop CARGO-BioID, a CRISPR-based TE-centric proteomics approach, to identify the proteins associated with thousands of copies of endogenous LTR7/HERV-H loci and potentially regulate their activity in hESCs. We found YTHDC2 and TET1 interact with each other and subsequently regulate m6A level on HERVH transcripts and 5hmC level on HERV-H genomic loci, which is critical for LTR7/HERV-H activities.
2023-05-12 | GSE210835 | GEO
Project description:Covalent modifications of RNA and DNA both regulate numerous biological processes, including development and cancer. The most abundant modification of RNA is that of N6-methyladenosine(m6A), while in the case of DNA, the CpG cytosine methylation characterizes cis-regulatory elements for spatial-temporal gene regulation. Recent studies establish a role for RNA m6A in regulating chromatin through histone modifications. However, whether there is also interplay between RNA and DNA methylation remains unknown. We address this question by studying regulation of the primate-specific transposable element (TE), LTR7/HERV-H, that is specifically activated in human embryonic stem cells (hESCs). Exploiting a novel proteomic approach, we find the RNA m6A-reader, YTHDC2, binds to LTR/HERV-H chromatin through interaction with m6A-modified HERV-H transcripts. Significantly, YTHDC2 recruits DNA demethylase, TET1, to activate LTR7/HERV-H via 5-hydroxymethycytosine(5hmC)-mediated DNA methylation. Furthermore, the YTHDC2/LTR7-axis prevents neural conversion of hESCs. Our results establish previously unknown crosstalk between RNA m6A and DNA methylation and new mechanisms controlling TE activity and hESC fate. We focused on the regulation of the primate-specific TE family, LTR7/HERV-H that is specifically active in the pluripotent human embryonic stem cells (hESCs) then silenced in differentiated lineages. We develop CARGO-BioID, a CRISPR-based TE-centric proteomics approach, to identify the proteins associated with thousands of copies of endogenous LTR7/HERV-H loci and potentially regulate their activity in hESCs. We found YTHDC2 and TET1 interact with each other and subsequently regulate m6A level on HERVH transcripts and 5hmC level on HERV-H genomic loci, which is critical for LTR7/HERV-H activities.
2023-05-12 | GSE210834 | GEO
Project description:Covalent modifications of RNA and DNA both regulate numerous biological processes, including development and cancer. The most abundant modification of RNA is that of N6-methyladenosine(m6A), while in the case of DNA, the CpG cytosine methylation characterizes cis-regulatory elements for spatial-temporal gene regulation. Recent studies establish a role for RNA m6A in regulating chromatin through histone modifications. However, whether there is also interplay between RNA and DNA methylation remains unknown. We address this question by studying regulation of the primate-specific transposable element (TE), LTR7/HERV-H, that is specifically activated in human embryonic stem cells (hESCs). Exploiting a novel proteomic approach, we find the RNA m6A-reader, YTHDC2, binds to LTR/HERV-H chromatin through interaction with m6A-modified HERV-H transcripts. Significantly, YTHDC2 recruits DNA demethylase, TET1, to activate LTR7/HERV-H via 5-hydroxymethycytosine(5hmC)-mediated DNA methylation. Furthermore, the YTHDC2/LTR7-axis prevents neural conversion of hESCs. Our results establish previously unknown crosstalk between RNA m6A and DNA methylation and new mechanisms controlling TE activity and hESC fate. We focused on the regulation of the primate-specific TE family, LTR7/HERV-H that is specifically active in the pluripotent human embryonic stem cells (hESCs) then silenced in differentiated lineages. We develop CARGO-BioID, a CRISPR-based TE-centric proteomics approach, to identify the proteins associated with thousands of copies of endogenous LTR7/HERV-H loci and potentially regulate their activity in hESCs. We found YTHDC2 and TET1 interact with each other and subsequently regulate m6A level on HERVH transcripts and 5hmC level on HERV-H genomic loci, which is critical for LTR7/HERV-H activities.
2023-05-12 | GSE210862 | GEO
Project description:Covalent modifications of RNA and DNA both regulate numerous biological processes, including development and cancer. The most abundant modification of RNA is that of N6-methyladenosine(m6A), while in the case of DNA, the CpG cytosine methylation characterizes cis-regulatory elements for spatial-temporal gene regulation. Recent studies establish a role for RNA m6A in regulating chromatin through histone modifications. However, whether there is also interplay between RNA and DNA methylation remains unknown. We address this question by studying regulation of the primate-specific transposable element (TE), LTR7/HERV-H, that is specifically activated in human embryonic stem cells (hESCs). Exploiting a novel proteomic approach, we find the RNA m6A-reader, YTHDC2, binds to LTR/HERV-H chromatin through interaction with m6A-modified HERV-H transcripts. Significantly, YTHDC2 recruits DNA demethylase, TET1, to activate LTR7/HERV-H via 5-hydroxymethycytosine(5hmC)-mediated DNA methylation. Furthermore, the YTHDC2/LTR7-axis prevents neural conversion of hESCs. Our results establish previously unknown crosstalk between RNA m6A and DNA methylation and new mechanisms controlling TE activity and hESC fate. We focused on the regulation of the primate-specific TE family, LTR7/HERV-H that is specifically active in the pluripotent human embryonic stem cells (hESCs) then silenced in differentiated lineages. We develop CARGO-BioID, a CRISPR-based TE-centric proteomics approach, to identify the proteins associated with thousands of copies of endogenous LTR7/HERV-H loci and potentially regulate their activity in hESCs. We found YTHDC2 and TET1 interact with each other and subsequently regulate m6A level on HERVH transcripts and 5hmC level on HERV-H genomic loci, which is critical for LTR7/HERV-H activities.
2023-05-12 | GSE210859 | GEO