Isoforms of the TAL1 transcription factor have different roles in hematopoiesis and cell growth.
Animals
Mice
Basic Helix-Loop-Helix Transcription Factors
/ genetics
Chromatin
Hematopoiesis
/ genetics
Precursor T-Cell Lymphoblastic Leukemia-Lymphoma
/ metabolism
Protein Isoforms
/ genetics
Proto-Oncogene Proteins
/ genetics
T-Cell Acute Lymphocytic Leukemia Protein 1
/ genetics
Transcription Factors
/ metabolism
Journal
PLoS biology
ISSN: 1545-7885
Titre abrégé: PLoS Biol
Pays: United States
ID NLM: 101183755
Informations de publication
Date de publication:
06 2023
06 2023
Historique:
received:
07
04
2023
accepted:
30
05
2023
revised:
11
07
2023
medline:
13
7
2023
pubmed:
28
6
2023
entrez:
28
6
2023
Statut:
epublish
Résumé
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.
Identifiants
pubmed: 37379322
doi: 10.1371/journal.pbio.3002175
pii: PBIOLOGY-D-23-00898
pmc: PMC10335695
doi:
Substances chimiques
Basic Helix-Loop-Helix Transcription Factors
0
Chromatin
0
Protein Isoforms
0
Proto-Oncogene Proteins
0
T-Cell Acute Lymphocytic Leukemia Protein 1
0
Transcription Factors
0
Tal1 protein, mouse
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
e3002175Informations de copyright
Copyright: © 2023 Sharma et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Déclaration de conflit d'intérêts
The authors have declared that no competing interests exist.
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