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Isoforms of the TAL1 transcription factor have different roles in hematopoiesis and cell growth

T-cell acute lymphoblastic leukemia (T-ALL) protein 1 (TAL1) is a central transcription factor in hematopoiesis. The timing and level of TAL1 expression orchestrate the differentiation to specialized blood cells and its overexpression is a common cause of T-ALL. Here, we studied the 2 protein isofor...

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Autores principales: Sharma, Aveksha, Mistriel-Zerbib, Shani, Najar, Rauf Ahmad, Engal, Eden, Bentata, Mercedes, Taqatqa, Nadeen, Dahan, Sara, Cohen, Klil, Jaffe-Herman, Shiri, Geminder, Ophir, Baker, Mai, Nevo, Yuval, Plaschkes, Inbar, Kay, Gillian, Drier, Yotam, Berger, Michael, Salton, Maayan
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10335695/
https://www.ncbi.nlm.nih.gov/pubmed/37379322
http://dx.doi.org/10.1371/journal.pbio.3002175
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author Sharma, Aveksha
Mistriel-Zerbib, Shani
Najar, Rauf Ahmad
Engal, Eden
Bentata, Mercedes
Taqatqa, Nadeen
Dahan, Sara
Cohen, Klil
Jaffe-Herman, Shiri
Geminder, Ophir
Baker, Mai
Nevo, Yuval
Plaschkes, Inbar
Kay, Gillian
Drier, Yotam
Berger, Michael
Salton, Maayan
author_facet Sharma, Aveksha
Mistriel-Zerbib, Shani
Najar, Rauf Ahmad
Engal, Eden
Bentata, Mercedes
Taqatqa, Nadeen
Dahan, Sara
Cohen, Klil
Jaffe-Herman, Shiri
Geminder, Ophir
Baker, Mai
Nevo, Yuval
Plaschkes, Inbar
Kay, Gillian
Drier, Yotam
Berger, Michael
Salton, Maayan
author_sort Sharma, Aveksha
collection PubMed
description T-cell acute lymphoblastic leukemia (T-ALL) protein 1 (TAL1) is a central transcription factor in hematopoiesis. The timing and level of TAL1 expression orchestrate the differentiation to specialized blood cells and its overexpression is a common cause of T-ALL. Here, we studied the 2 protein isoforms of TAL1, short and long, which are generated by the use of alternative promoters as well as by alternative splicing. We analyzed the expression of each isoform by deleting an enhancer or insulator, or by opening chromatin at the enhancer location. Our results show that each enhancer promotes expression from a specific TAL1 promoter. Expression from a specific promoter gives rise to a unique 5′ UTR with differential regulation of translation. Moreover, our study suggests that the enhancers regulate TAL1 exon 3 alternative splicing by inducing changes in the chromatin at the splice site, which we demonstrate is mediated by KMT2B. Furthermore, our results indicate that TAL1-short binds more strongly to TAL1 E-protein partners and functions as a stronger transcription factor than TAL1-long. Specifically TAL1-short has a unique transcription signature promoting apoptosis. Finally, when we expressed both isoforms in mice bone marrow, we found that while overexpression of both isoforms prevents lymphoid differentiation, expression of TAL1-short alone leads to hematopoietic stem cell exhaustion. Furthermore, we found that TAL1-short promoted erythropoiesis and reduced cell survival in the CML cell line K562. While TAL1 and its partners are considered promising therapeutic targets in the treatment of T-ALL, our results show that TAL1-short could act as a tumor suppressor and suggest that altering TAL1 isoform’s ratio could be a preferred therapeutic approach.
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spelling pubmed-103356952023-07-12 Isoforms of the TAL1 transcription factor have different roles in hematopoiesis and cell growth Sharma, Aveksha Mistriel-Zerbib, Shani Najar, Rauf Ahmad Engal, Eden Bentata, Mercedes Taqatqa, Nadeen Dahan, Sara Cohen, Klil Jaffe-Herman, Shiri Geminder, Ophir Baker, Mai Nevo, Yuval Plaschkes, Inbar Kay, Gillian Drier, Yotam Berger, Michael Salton, Maayan PLoS Biol Research Article T-cell acute lymphoblastic leukemia (T-ALL) protein 1 (TAL1) is a central transcription factor in hematopoiesis. The timing and level of TAL1 expression orchestrate the differentiation to specialized blood cells and its overexpression is a common cause of T-ALL. Here, we studied the 2 protein isoforms of TAL1, short and long, which are generated by the use of alternative promoters as well as by alternative splicing. We analyzed the expression of each isoform by deleting an enhancer or insulator, or by opening chromatin at the enhancer location. Our results show that each enhancer promotes expression from a specific TAL1 promoter. Expression from a specific promoter gives rise to a unique 5′ UTR with differential regulation of translation. Moreover, our study suggests that the enhancers regulate TAL1 exon 3 alternative splicing by inducing changes in the chromatin at the splice site, which we demonstrate is mediated by KMT2B. Furthermore, our results indicate that TAL1-short binds more strongly to TAL1 E-protein partners and functions as a stronger transcription factor than TAL1-long. Specifically TAL1-short has a unique transcription signature promoting apoptosis. Finally, when we expressed both isoforms in mice bone marrow, we found that while overexpression of both isoforms prevents lymphoid differentiation, expression of TAL1-short alone leads to hematopoietic stem cell exhaustion. Furthermore, we found that TAL1-short promoted erythropoiesis and reduced cell survival in the CML cell line K562. While TAL1 and its partners are considered promising therapeutic targets in the treatment of T-ALL, our results show that TAL1-short could act as a tumor suppressor and suggest that altering TAL1 isoform’s ratio could be a preferred therapeutic approach. Public Library of Science 2023-06-28 /pmc/articles/PMC10335695/ /pubmed/37379322 http://dx.doi.org/10.1371/journal.pbio.3002175 Text en © 2023 Sharma et al https://creativecommons.org/licenses/by/4.0/This is an open access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
spellingShingle Research Article
Sharma, Aveksha
Mistriel-Zerbib, Shani
Najar, Rauf Ahmad
Engal, Eden
Bentata, Mercedes
Taqatqa, Nadeen
Dahan, Sara
Cohen, Klil
Jaffe-Herman, Shiri
Geminder, Ophir
Baker, Mai
Nevo, Yuval
Plaschkes, Inbar
Kay, Gillian
Drier, Yotam
Berger, Michael
Salton, Maayan
Isoforms of the TAL1 transcription factor have different roles in hematopoiesis and cell growth
title Isoforms of the TAL1 transcription factor have different roles in hematopoiesis and cell growth
title_full Isoforms of the TAL1 transcription factor have different roles in hematopoiesis and cell growth
title_fullStr Isoforms of the TAL1 transcription factor have different roles in hematopoiesis and cell growth
title_full_unstemmed Isoforms of the TAL1 transcription factor have different roles in hematopoiesis and cell growth
title_short Isoforms of the TAL1 transcription factor have different roles in hematopoiesis and cell growth
title_sort isoforms of the tal1 transcription factor have different roles in hematopoiesis and cell growth
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10335695/
https://www.ncbi.nlm.nih.gov/pubmed/37379322
http://dx.doi.org/10.1371/journal.pbio.3002175
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