PML::RARA and GATA2 proteins interact via DNA templates to induce aberrant self-renewal in mouse and human hematopoietic cells.
Proc Natl Acad Sci U S A
; 121(18): e2317690121, 2024 Apr 30.
Article
em En
| MEDLINE
| ID: mdl-38648485
ABSTRACT
The underlying mechanism(s) by which the PMLRARA fusion protein initiates acute promyelocytic leukemia is not yet clear. We defined the genomic binding sites of PMLRARA in primary mouse and human hematopoietic progenitor cells with V5-tagged PMLRARA, using anti-V5-PMLRARA chromatin immunoprecipitation sequencing and CUT&RUN approaches. Most genomic PMLRARA binding sites were found in regions that were already chromatin-accessible (defined by ATAC-seq) in unmanipulated, wild-type promyelocytes, suggesting that these regions are "open" prior to PMLRARA expression. We found that GATA binding motifs, and the direct binding of the chromatin "pioneering factor" GATA2, were significantly enriched near PMLRARA binding sites. Proximity labeling studies revealed that PMLRARA interacts with ~250 proteins in primary mouse hematopoietic cells; GATA2 and 33 others require PMLRARA binding to DNA for the interaction to occur, suggesting that binding to their cognate DNA target motifs may stabilize their interactions. In the absence of PMLRARA, Gata2 overexpression induces many of the same epigenetic and transcriptional changes as PMLRARA. These findings suggested that PMLRARA may indirectly initiate its transcriptional program by activating Gata2 expression Indeed, we demonstrated that inactivation of Gata2 prior to PMLRARA expression prevented its ability to induce self-renewal. These data suggested that GATA2 binding creates accessible chromatin regions enriched for both GATA and Retinoic Acid Receptor Element motifs, where GATA2 and PMLRARA can potentially bind and interact with each other. In turn, PMLRARA binding to DNA promotes a feed-forward transcriptional program by positively regulating Gata2 expression. Gata2 may therefore be required for PMLRARA to establish its transcriptional program.
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Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Células-Tronco Hematopoéticas
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Proteínas de Fusão Oncogênica
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Fator de Transcrição GATA2
Limite:
Animals
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Humans
Idioma:
En
Revista:
Proc Natl Acad Sci U S A
Ano de publicação:
2024
Tipo de documento:
Article