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Epigenetic Drug Treatment Globally Induces Cryptic Transcription Start Sites Encoded in Long Terminal Repeats
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| Zeitschriftentitel: | Blood |
|---|---|
| Personen und Körperschaften: | , , , , , , , , , , , , , , , , , , , , , , , , , |
| In: | Blood, 128, 2016, 22, S. 3931-3931 |
| Format: | E-Article |
| Sprache: | Englisch |
| veröffentlicht: |
American Society of Hematology
|
| Schlagwörter: |
| author_facet |
Daskalakis, Michael Brocks, David Schmidt, Christopher Li, Daofeng Li, Jing Jang, Hyo S. Zhang, Bo Lipka, Daniel B Schott, Johanna Bierhoff, Holger Assenov, Yassen Helf, Monika Ressnerova, Alzbeta Lindroth, Anders Haas, Simon Essers, Marieke A. G. Imbusch, Charles D. Brors, Benedikt Oehme, Ina Witt, Olaf Lübbert, Michael Stoecklin, Georg Gerhäuser, Clarissa Oakes, Christopher C Wang, Ting Plass, Christoph Daskalakis, Michael Brocks, David Schmidt, Christopher Li, Daofeng Li, Jing Jang, Hyo S. Zhang, Bo Lipka, Daniel B Schott, Johanna Bierhoff, Holger Assenov, Yassen Helf, Monika Ressnerova, Alzbeta Lindroth, Anders Haas, Simon Essers, Marieke A. G. Imbusch, Charles D. Brors, Benedikt Oehme, Ina Witt, Olaf Lübbert, Michael Stoecklin, Georg Gerhäuser, Clarissa Oakes, Christopher C Wang, Ting Plass, Christoph |
|---|---|
| author |
Daskalakis, Michael Brocks, David Schmidt, Christopher Li, Daofeng Li, Jing Jang, Hyo S. Zhang, Bo Lipka, Daniel B Schott, Johanna Bierhoff, Holger Assenov, Yassen Helf, Monika Ressnerova, Alzbeta Lindroth, Anders Haas, Simon Essers, Marieke A. G. Imbusch, Charles D. Brors, Benedikt Oehme, Ina Witt, Olaf Lübbert, Michael Stoecklin, Georg Gerhäuser, Clarissa Oakes, Christopher C Wang, Ting Plass, Christoph |
| spellingShingle |
Daskalakis, Michael Brocks, David Schmidt, Christopher Li, Daofeng Li, Jing Jang, Hyo S. Zhang, Bo Lipka, Daniel B Schott, Johanna Bierhoff, Holger Assenov, Yassen Helf, Monika Ressnerova, Alzbeta Lindroth, Anders Haas, Simon Essers, Marieke A. G. Imbusch, Charles D. Brors, Benedikt Oehme, Ina Witt, Olaf Lübbert, Michael Stoecklin, Georg Gerhäuser, Clarissa Oakes, Christopher C Wang, Ting Plass, Christoph Blood Epigenetic Drug Treatment Globally Induces Cryptic Transcription Start Sites Encoded in Long Terminal Repeats Cell Biology Hematology Immunology Biochemistry |
| author_sort |
daskalakis, michael |
| spelling |
Daskalakis, Michael Brocks, David Schmidt, Christopher Li, Daofeng Li, Jing Jang, Hyo S. Zhang, Bo Lipka, Daniel B Schott, Johanna Bierhoff, Holger Assenov, Yassen Helf, Monika Ressnerova, Alzbeta Lindroth, Anders Haas, Simon Essers, Marieke A. G. Imbusch, Charles D. Brors, Benedikt Oehme, Ina Witt, Olaf Lübbert, Michael Stoecklin, Georg Gerhäuser, Clarissa Oakes, Christopher C Wang, Ting Plass, Christoph 0006-4971 1528-0020 American Society of Hematology Cell Biology Hematology Immunology Biochemistry http://dx.doi.org/10.1182/blood.v128.22.3931.3931 <jats:title>Abstract</jats:title> <jats:p>Epigenetic drugs are currently used for the treatment of several hematologic malignancies, but their mechanism of action remains poorly understood. By using a previously described reporter cell line for epigenetic reactivation of the DAPK1 locus, we have shown that epigenetic treatment causes transcription from uncharacterized intronic transcription start sites (TSSs), thereby generating DAPK1 mRNA with novel first exons. Based on these findings, we analyzed whether inhibition of DNA-Methyltransferases (DNMTs), Histone deacetylases (HDACs), or both resulted in the genome-wide induction of non-canonical TSSs. While epigenetic treatment altered expression of known promoter sites, we observed that both HDAC- and DNMT-inhibitors predominantly induced de novo transcription from cryptic promoters encoded in long-terminal repeat (LTR) retrotransposons. These LTR-associated 'treatment induced, not-annotated TSS' (TINATs) are currently not annotated and normally silenced in almost all cell types with the exception of testicular und thymic tissue. In the majority of cases, these TINATs arose most commonly from LTR12 elements, particularly LTR12C (which apparently provides 50% of all TINATs). TINAT activation after DNMT-inhibitors (DNMTi) coincided with DNA hypomethylation and gain in H3K4me3, H3K9ac, and H3K27ac histone marks. In contrast, HDAC-inhibitors (HDACi) induced only canonical TSSs in association with histone acetylation, but TINATs via a yet unknown mechanism. Nevertheless, both inhibitors convergently induced unidirectional transcription from identical TINAT sites. Moreover, we found a consensus GATA2 binding motif which strongly distinguished LTR12Cs with TINATs from LTR12Cs without TINATs, supporting that GATA2 is likely the upstream transcription factor responsible for TINAT activation. TINATs originating from non-canonical TSSs located within introns of protein-coding genes frequently spliced into downstream exons thereby creating LTR/non-LTR fusion transcripts that harbor novel in place of canonical exon sequence at their 5' end. The resulting transcripts encode truncated or chimeric open reading frames which translated into currently uncharacterized protein isoforms with predicted abnormal functions or immunogenic potential, the last one based on their foreign sequence and capability of being presented on MHC-class I molecules. In summary, we could show that DNMTi and/or HDACi do not predominantly alter the expression of canonical genes, but induce de novo transcription of LTRs especially of the LTR12 family, resulting in numerous fusion transcripts that encode novel protein isoforms which might have the potential to influence cell proliferation or might be an elegant explanation for the priming effect of epigenetic therapy. Ongoing experiments are investigating the functional mechanisms of TINAT reactivation upon epigenetic drug treatment and future proteomic approaches combined with T-cell cytotoxicity assays will further shed light on the interaction between epigenetic and immune therapy and the role of ERV-derived antigen presentation.</jats:p> <jats:sec> <jats:title>Disclosures</jats:title> <jats:p>Lübbert: Janssen-Cilag: Other: Travel Funding, Research Funding; Ratiopharm: Other: Study drug valproic acid; Celgene: Other: Travel Funding.</jats:p> </jats:sec> Epigenetic Drug Treatment Globally Induces Cryptic Transcription Start Sites Encoded in Long Terminal Repeats Blood |
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American Society of Hematology, 2016 |
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American Society of Hematology, 2016 |
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2016 |
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American Society of Hematology |
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| title |
Epigenetic Drug Treatment Globally Induces Cryptic Transcription Start Sites Encoded in Long Terminal Repeats |
| title_unstemmed |
Epigenetic Drug Treatment Globally Induces Cryptic Transcription Start Sites Encoded in Long Terminal Repeats |
| title_full |
Epigenetic Drug Treatment Globally Induces Cryptic Transcription Start Sites Encoded in Long Terminal Repeats |
| title_fullStr |
Epigenetic Drug Treatment Globally Induces Cryptic Transcription Start Sites Encoded in Long Terminal Repeats |
| title_full_unstemmed |
Epigenetic Drug Treatment Globally Induces Cryptic Transcription Start Sites Encoded in Long Terminal Repeats |
| title_short |
Epigenetic Drug Treatment Globally Induces Cryptic Transcription Start Sites Encoded in Long Terminal Repeats |
| title_sort |
epigenetic drug treatment globally induces cryptic transcription start sites encoded in long terminal repeats |
| topic |
Cell Biology Hematology Immunology Biochemistry |
| url |
http://dx.doi.org/10.1182/blood.v128.22.3931.3931 |
| publishDate |
2016 |
| physical |
3931-3931 |
| description |
<jats:title>Abstract</jats:title>
<jats:p>Epigenetic drugs are currently used for the treatment of several hematologic malignancies, but their mechanism of action remains poorly understood. By using a previously described reporter cell line for epigenetic reactivation of the DAPK1 locus, we have shown that epigenetic treatment causes transcription from uncharacterized intronic transcription start sites (TSSs), thereby generating DAPK1 mRNA with novel first exons. Based on these findings, we analyzed whether inhibition of DNA-Methyltransferases (DNMTs), Histone deacetylases (HDACs), or both resulted in the genome-wide induction of non-canonical TSSs. While epigenetic treatment altered expression of known promoter sites, we observed that both HDAC- and DNMT-inhibitors predominantly induced de novo transcription from cryptic promoters encoded in long-terminal repeat (LTR) retrotransposons. These LTR-associated 'treatment induced, not-annotated TSS' (TINATs) are currently not annotated and normally silenced in almost all cell types with the exception of testicular und thymic tissue. In the majority of cases, these TINATs arose most commonly from LTR12 elements, particularly LTR12C (which apparently provides 50% of all TINATs). TINAT activation after DNMT-inhibitors (DNMTi) coincided with DNA hypomethylation and gain in H3K4me3, H3K9ac, and H3K27ac histone marks. In contrast, HDAC-inhibitors (HDACi) induced only canonical TSSs in association with histone acetylation, but TINATs via a yet unknown mechanism. Nevertheless, both inhibitors convergently induced unidirectional transcription from identical TINAT sites. Moreover, we found a consensus GATA2 binding motif which strongly distinguished LTR12Cs with TINATs from LTR12Cs without TINATs, supporting that GATA2 is likely the upstream transcription factor responsible for TINAT activation. TINATs originating from non-canonical TSSs located within introns of protein-coding genes frequently spliced into downstream exons thereby creating LTR/non-LTR fusion transcripts that harbor novel in place of canonical exon sequence at their 5' end. The resulting transcripts encode truncated or chimeric open reading frames which translated into currently uncharacterized protein isoforms with predicted abnormal functions or immunogenic potential, the last one based on their foreign sequence and capability of being presented on MHC-class I molecules. In summary, we could show that DNMTi and/or HDACi do not predominantly alter the expression of canonical genes, but induce de novo transcription of LTRs especially of the LTR12 family, resulting in numerous fusion transcripts that encode novel protein isoforms which might have the potential to influence cell proliferation or might be an elegant explanation for the priming effect of epigenetic therapy. Ongoing experiments are investigating the functional mechanisms of TINAT reactivation upon epigenetic drug treatment and future proteomic approaches combined with T-cell cytotoxicity assays will further shed light on the interaction between epigenetic and immune therapy and the role of ERV-derived antigen presentation.</jats:p>
<jats:sec>
<jats:title>Disclosures</jats:title>
<jats:p>Lübbert: Janssen-Cilag: Other: Travel Funding, Research Funding; Ratiopharm: Other: Study drug valproic acid; Celgene: Other: Travel Funding.</jats:p>
</jats:sec> |
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| author | Daskalakis, Michael, Brocks, David, Schmidt, Christopher, Li, Daofeng, Li, Jing, Jang, Hyo S., Zhang, Bo, Lipka, Daniel B, Schott, Johanna, Bierhoff, Holger, Assenov, Yassen, Helf, Monika, Ressnerova, Alzbeta, Lindroth, Anders, Haas, Simon, Essers, Marieke A. G., Imbusch, Charles D., Brors, Benedikt, Oehme, Ina, Witt, Olaf, Lübbert, Michael, Stoecklin, Georg, Gerhäuser, Clarissa, Oakes, Christopher C, Wang, Ting, Plass, Christoph |
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| description | <jats:title>Abstract</jats:title> <jats:p>Epigenetic drugs are currently used for the treatment of several hematologic malignancies, but their mechanism of action remains poorly understood. By using a previously described reporter cell line for epigenetic reactivation of the DAPK1 locus, we have shown that epigenetic treatment causes transcription from uncharacterized intronic transcription start sites (TSSs), thereby generating DAPK1 mRNA with novel first exons. Based on these findings, we analyzed whether inhibition of DNA-Methyltransferases (DNMTs), Histone deacetylases (HDACs), or both resulted in the genome-wide induction of non-canonical TSSs. While epigenetic treatment altered expression of known promoter sites, we observed that both HDAC- and DNMT-inhibitors predominantly induced de novo transcription from cryptic promoters encoded in long-terminal repeat (LTR) retrotransposons. These LTR-associated 'treatment induced, not-annotated TSS' (TINATs) are currently not annotated and normally silenced in almost all cell types with the exception of testicular und thymic tissue. In the majority of cases, these TINATs arose most commonly from LTR12 elements, particularly LTR12C (which apparently provides 50% of all TINATs). TINAT activation after DNMT-inhibitors (DNMTi) coincided with DNA hypomethylation and gain in H3K4me3, H3K9ac, and H3K27ac histone marks. In contrast, HDAC-inhibitors (HDACi) induced only canonical TSSs in association with histone acetylation, but TINATs via a yet unknown mechanism. Nevertheless, both inhibitors convergently induced unidirectional transcription from identical TINAT sites. Moreover, we found a consensus GATA2 binding motif which strongly distinguished LTR12Cs with TINATs from LTR12Cs without TINATs, supporting that GATA2 is likely the upstream transcription factor responsible for TINAT activation. TINATs originating from non-canonical TSSs located within introns of protein-coding genes frequently spliced into downstream exons thereby creating LTR/non-LTR fusion transcripts that harbor novel in place of canonical exon sequence at their 5' end. The resulting transcripts encode truncated or chimeric open reading frames which translated into currently uncharacterized protein isoforms with predicted abnormal functions or immunogenic potential, the last one based on their foreign sequence and capability of being presented on MHC-class I molecules. In summary, we could show that DNMTi and/or HDACi do not predominantly alter the expression of canonical genes, but induce de novo transcription of LTRs especially of the LTR12 family, resulting in numerous fusion transcripts that encode novel protein isoforms which might have the potential to influence cell proliferation or might be an elegant explanation for the priming effect of epigenetic therapy. Ongoing experiments are investigating the functional mechanisms of TINAT reactivation upon epigenetic drug treatment and future proteomic approaches combined with T-cell cytotoxicity assays will further shed light on the interaction between epigenetic and immune therapy and the role of ERV-derived antigen presentation.</jats:p> <jats:sec> <jats:title>Disclosures</jats:title> <jats:p>Lübbert: Janssen-Cilag: Other: Travel Funding, Research Funding; Ratiopharm: Other: Study drug valproic acid; Celgene: Other: Travel Funding.</jats:p> </jats:sec> |
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| spelling | Daskalakis, Michael Brocks, David Schmidt, Christopher Li, Daofeng Li, Jing Jang, Hyo S. Zhang, Bo Lipka, Daniel B Schott, Johanna Bierhoff, Holger Assenov, Yassen Helf, Monika Ressnerova, Alzbeta Lindroth, Anders Haas, Simon Essers, Marieke A. G. Imbusch, Charles D. Brors, Benedikt Oehme, Ina Witt, Olaf Lübbert, Michael Stoecklin, Georg Gerhäuser, Clarissa Oakes, Christopher C Wang, Ting Plass, Christoph 0006-4971 1528-0020 American Society of Hematology Cell Biology Hematology Immunology Biochemistry http://dx.doi.org/10.1182/blood.v128.22.3931.3931 <jats:title>Abstract</jats:title> <jats:p>Epigenetic drugs are currently used for the treatment of several hematologic malignancies, but their mechanism of action remains poorly understood. By using a previously described reporter cell line for epigenetic reactivation of the DAPK1 locus, we have shown that epigenetic treatment causes transcription from uncharacterized intronic transcription start sites (TSSs), thereby generating DAPK1 mRNA with novel first exons. Based on these findings, we analyzed whether inhibition of DNA-Methyltransferases (DNMTs), Histone deacetylases (HDACs), or both resulted in the genome-wide induction of non-canonical TSSs. While epigenetic treatment altered expression of known promoter sites, we observed that both HDAC- and DNMT-inhibitors predominantly induced de novo transcription from cryptic promoters encoded in long-terminal repeat (LTR) retrotransposons. These LTR-associated 'treatment induced, not-annotated TSS' (TINATs) are currently not annotated and normally silenced in almost all cell types with the exception of testicular und thymic tissue. In the majority of cases, these TINATs arose most commonly from LTR12 elements, particularly LTR12C (which apparently provides 50% of all TINATs). TINAT activation after DNMT-inhibitors (DNMTi) coincided with DNA hypomethylation and gain in H3K4me3, H3K9ac, and H3K27ac histone marks. In contrast, HDAC-inhibitors (HDACi) induced only canonical TSSs in association with histone acetylation, but TINATs via a yet unknown mechanism. Nevertheless, both inhibitors convergently induced unidirectional transcription from identical TINAT sites. Moreover, we found a consensus GATA2 binding motif which strongly distinguished LTR12Cs with TINATs from LTR12Cs without TINATs, supporting that GATA2 is likely the upstream transcription factor responsible for TINAT activation. TINATs originating from non-canonical TSSs located within introns of protein-coding genes frequently spliced into downstream exons thereby creating LTR/non-LTR fusion transcripts that harbor novel in place of canonical exon sequence at their 5' end. The resulting transcripts encode truncated or chimeric open reading frames which translated into currently uncharacterized protein isoforms with predicted abnormal functions or immunogenic potential, the last one based on their foreign sequence and capability of being presented on MHC-class I molecules. In summary, we could show that DNMTi and/or HDACi do not predominantly alter the expression of canonical genes, but induce de novo transcription of LTRs especially of the LTR12 family, resulting in numerous fusion transcripts that encode novel protein isoforms which might have the potential to influence cell proliferation or might be an elegant explanation for the priming effect of epigenetic therapy. Ongoing experiments are investigating the functional mechanisms of TINAT reactivation upon epigenetic drug treatment and future proteomic approaches combined with T-cell cytotoxicity assays will further shed light on the interaction between epigenetic and immune therapy and the role of ERV-derived antigen presentation.</jats:p> <jats:sec> <jats:title>Disclosures</jats:title> <jats:p>Lübbert: Janssen-Cilag: Other: Travel Funding, Research Funding; Ratiopharm: Other: Study drug valproic acid; Celgene: Other: Travel Funding.</jats:p> </jats:sec> Epigenetic Drug Treatment Globally Induces Cryptic Transcription Start Sites Encoded in Long Terminal Repeats Blood |
| spellingShingle | Daskalakis, Michael, Brocks, David, Schmidt, Christopher, Li, Daofeng, Li, Jing, Jang, Hyo S., Zhang, Bo, Lipka, Daniel B, Schott, Johanna, Bierhoff, Holger, Assenov, Yassen, Helf, Monika, Ressnerova, Alzbeta, Lindroth, Anders, Haas, Simon, Essers, Marieke A. G., Imbusch, Charles D., Brors, Benedikt, Oehme, Ina, Witt, Olaf, Lübbert, Michael, Stoecklin, Georg, Gerhäuser, Clarissa, Oakes, Christopher C, Wang, Ting, Plass, Christoph, Blood, Epigenetic Drug Treatment Globally Induces Cryptic Transcription Start Sites Encoded in Long Terminal Repeats, Cell Biology, Hematology, Immunology, Biochemistry |
| title | Epigenetic Drug Treatment Globally Induces Cryptic Transcription Start Sites Encoded in Long Terminal Repeats |
| title_full | Epigenetic Drug Treatment Globally Induces Cryptic Transcription Start Sites Encoded in Long Terminal Repeats |
| title_fullStr | Epigenetic Drug Treatment Globally Induces Cryptic Transcription Start Sites Encoded in Long Terminal Repeats |
| title_full_unstemmed | Epigenetic Drug Treatment Globally Induces Cryptic Transcription Start Sites Encoded in Long Terminal Repeats |
| title_short | Epigenetic Drug Treatment Globally Induces Cryptic Transcription Start Sites Encoded in Long Terminal Repeats |
| title_sort | epigenetic drug treatment globally induces cryptic transcription start sites encoded in long terminal repeats |
| title_unstemmed | Epigenetic Drug Treatment Globally Induces Cryptic Transcription Start Sites Encoded in Long Terminal Repeats |
| topic | Cell Biology, Hematology, Immunology, Biochemistry |
| url | http://dx.doi.org/10.1182/blood.v128.22.3931.3931 |