Polysome-CAGE of TCL1-driven chronic lymphocytic leukemia revealed multiple N-terminally altered epigenetic regulators and a translation stress signature
The transformation of normal to malignant cells is accompanied by substantial changes in gene expression programs through diverse mechanisms. Here, we examined the changes in the landscape of transcription start sites and alternative promoter (AP) usage and their impact on the translatome in TCL1-dr...
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| Format: | Article |
| Language: | English |
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eLife Sciences Publications Ltd
2022-08-01
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| Series: | eLife |
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| Online Access: | https://elifesciences.org/articles/77714 |
| _version_ | 1828374826802216960 |
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| author | Ariel Ogran Tal Havkin-Solomon Shirly Becker-Herman Keren David Idit Shachar Rivka Dikstein |
| author_facet | Ariel Ogran Tal Havkin-Solomon Shirly Becker-Herman Keren David Idit Shachar Rivka Dikstein |
| author_sort | Ariel Ogran |
| collection | DOAJ |
| description | The transformation of normal to malignant cells is accompanied by substantial changes in gene expression programs through diverse mechanisms. Here, we examined the changes in the landscape of transcription start sites and alternative promoter (AP) usage and their impact on the translatome in TCL1-driven chronic lymphocytic leukemia (CLL). Our findings revealed a marked elevation of APs in CLL B cells from Eµ-Tcl1 transgenic mice, which are particularly enriched with intra-genic promoters that generate N-terminally truncated or modified proteins. Intra-genic promoter activation is mediated by (1) loss of function of ‘closed chromatin’ epigenetic regulators due to the generation of inactive N-terminally modified isoforms or reduced expression; (2) upregulation of transcription factors, including c-Myc, targeting the intra-genic promoters and their associated enhancers. Exogenous expression of Tcl1 in MEFs is sufficient to induce intra-genic promoters of epigenetic regulators and promote c-Myc expression. We further found a dramatic translation downregulation of transcripts bearing CNY cap-proximal trinucleotides, reminiscent of cells undergoing metabolic stress. These findings uncovered the role of Tcl1 oncogenic function in altering promoter usage and mRNA translation in leukemogenesis. |
| first_indexed | 2024-04-14T07:38:22Z |
| format | Article |
| id | doaj.art-4a07f29a457d4718a1b3bfb50f6d062c |
| institution | Directory Open Access Journal |
| issn | 2050-084X |
| language | English |
| last_indexed | 2024-04-14T07:38:22Z |
| publishDate | 2022-08-01 |
| publisher | eLife Sciences Publications Ltd |
| record_format | Article |
| series | eLife |
| spelling | doaj.art-4a07f29a457d4718a1b3bfb50f6d062c2022-12-22T02:05:36ZengeLife Sciences Publications LtdeLife2050-084X2022-08-011110.7554/eLife.77714Polysome-CAGE of TCL1-driven chronic lymphocytic leukemia revealed multiple N-terminally altered epigenetic regulators and a translation stress signatureAriel Ogran0https://orcid.org/0000-0002-9411-3537Tal Havkin-Solomon1Shirly Becker-Herman2Keren David3Idit Shachar4Rivka Dikstein5https://orcid.org/0000-0002-6251-4723Department of Biomolecular Sciences, The Weizmann Institute of Science, Rehovot, IsraelDepartment of Biomolecular Sciences, The Weizmann Institute of Science, Rehovot, IsraelDepartment of Immunology, The Weizmann Institute of Science, Rehovot, IsraelDepartment of Immunology, The Weizmann Institute of Science, Rehovot, IsraelDepartment of Immunology, The Weizmann Institute of Science, Rehovot, IsraelDepartment of Biomolecular Sciences, The Weizmann Institute of Science, Rehovot, IsraelThe transformation of normal to malignant cells is accompanied by substantial changes in gene expression programs through diverse mechanisms. Here, we examined the changes in the landscape of transcription start sites and alternative promoter (AP) usage and their impact on the translatome in TCL1-driven chronic lymphocytic leukemia (CLL). Our findings revealed a marked elevation of APs in CLL B cells from Eµ-Tcl1 transgenic mice, which are particularly enriched with intra-genic promoters that generate N-terminally truncated or modified proteins. Intra-genic promoter activation is mediated by (1) loss of function of ‘closed chromatin’ epigenetic regulators due to the generation of inactive N-terminally modified isoforms or reduced expression; (2) upregulation of transcription factors, including c-Myc, targeting the intra-genic promoters and their associated enhancers. Exogenous expression of Tcl1 in MEFs is sufficient to induce intra-genic promoters of epigenetic regulators and promote c-Myc expression. We further found a dramatic translation downregulation of transcripts bearing CNY cap-proximal trinucleotides, reminiscent of cells undergoing metabolic stress. These findings uncovered the role of Tcl1 oncogenic function in altering promoter usage and mRNA translation in leukemogenesis.https://elifesciences.org/articles/77714alternative promoterTCL1translationCLLtranscription start sitepolysome-CAGE |
| spellingShingle | Ariel Ogran Tal Havkin-Solomon Shirly Becker-Herman Keren David Idit Shachar Rivka Dikstein Polysome-CAGE of TCL1-driven chronic lymphocytic leukemia revealed multiple N-terminally altered epigenetic regulators and a translation stress signature eLife alternative promoter TCL1 translation CLL transcription start site polysome-CAGE |
| title | Polysome-CAGE of TCL1-driven chronic lymphocytic leukemia revealed multiple N-terminally altered epigenetic regulators and a translation stress signature |
| title_full | Polysome-CAGE of TCL1-driven chronic lymphocytic leukemia revealed multiple N-terminally altered epigenetic regulators and a translation stress signature |
| title_fullStr | Polysome-CAGE of TCL1-driven chronic lymphocytic leukemia revealed multiple N-terminally altered epigenetic regulators and a translation stress signature |
| title_full_unstemmed | Polysome-CAGE of TCL1-driven chronic lymphocytic leukemia revealed multiple N-terminally altered epigenetic regulators and a translation stress signature |
| title_short | Polysome-CAGE of TCL1-driven chronic lymphocytic leukemia revealed multiple N-terminally altered epigenetic regulators and a translation stress signature |
| title_sort | polysome cage of tcl1 driven chronic lymphocytic leukemia revealed multiple n terminally altered epigenetic regulators and a translation stress signature |
| topic | alternative promoter TCL1 translation CLL transcription start site polysome-CAGE |
| url | https://elifesciences.org/articles/77714 |
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