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1.
EMBO J ; 42(3): e112058, 2023 02 01.
Artículo en Inglés | MEDLINE | ID: mdl-36524443

RESUMEN

TRIM33 is a chromatin reader required for mammalian mesendoderm differentiation after activation of Nodal signaling, while its role in mESCs is still elusive. Here, we report that TRIM33 co-localizes with promyelocytic leukemia nuclear bodies (PML-NBs) specifically in mESCs, to mediate Nodal signaling-directed transcription of Lefty1/2. We show that TRIM33 puncta formation in mESCs depends on PML and on specific assembly of PML-NBs. Moreover, TRIM33 and PML co-regulate Lefty1/2 expression in mESCs, with both PML protein and formation of mESCs-specific PML-NBs being required for TRIM33 recruitment to these loci, and PML-NBs directly associating with the Lefty1/2 loci. Finally, a TurboID proximity-labeling experiment confirmed that TRIM33 is highly enriched only in mESCs-specific PML-NBs. Thus, our study supports a model in which TRIM33 condensates regulate Nodal signaling-directed transcription in mESCs and shows that PML-NBs can recruit distinct sets of client proteins in a cell-context-dependent manner.


Asunto(s)
Células Madre Embrionarias de Ratones , Cuerpos Nucleares de la Leucemia Promielocítica , Animales , Humanos , Proteína de la Leucemia Promielocítica/genética , Proteína de la Leucemia Promielocítica/metabolismo , Células Madre Embrionarias de Ratones/metabolismo , Proteínas Nucleares/genética , Proteínas Nucleares/metabolismo , Transducción de Señal , Núcleo Celular/metabolismo , Mamíferos , Factores de Transcripción/genética
2.
Nucleic Acids Res ; 50(18): 10526-10543, 2022 10 14.
Artículo en Inglés | MEDLINE | ID: mdl-36134711

RESUMEN

Transforming growth factor ß (TGF-ß) superfamily proteins are potent regulators of cellular development and differentiation. Nodal/Activin/TGF-ß and BMP ligands are both present in the intra- and extracellular milieu during early development, and cross-talk between these two branches of developmental signaling is currently the subject of intense research focus. Here, we show that the Nodal induced lncRNA-Smad7 regulates cell fate determination via repression of BMP signaling in mouse embryonic stem cells (mESCs). Depletion of lncRNA-Smad7 dramatically impairs cardiomyocyte differentiation in mESCs. Moreover, lncRNA-Smad7 represses Bmp2 expression through binding with the Bmp2 promoter region via (CA)12-repeats that forms an R-loop. Importantly, Bmp2 knockdown rescues defects in cardiomyocyte differentiation induced by lncRNA-Smad7 knockdown. Hence, lncRNA-Smad7 antagonizes BMP signaling in mESCs, and similarly regulates cell fate determination between osteocyte and myocyte formation in C2C12 mouse myoblasts. Moreover, lncRNA-Smad7 associates with hnRNPK in mESCs and hnRNPK binds at the Bmp2 promoter, potentially contributing to Bmp2 expression repression. The antagonistic effects between Nodal/TGF-ß and BMP signaling via lncRNA-Smad7 described in this work provides a framework for understanding cell fate determination in early development.


Asunto(s)
ARN Largo no Codificante , Proteína smad7/metabolismo , Activinas/metabolismo , Activinas/farmacología , Animales , Diferenciación Celular , Ligandos , Ratones , ARN Largo no Codificante/metabolismo , Proteína smad7/genética , Proteína smad7/farmacología , Factor de Crecimiento Transformador beta/metabolismo
3.
Stem Cell Reports ; 13(4): 642-656, 2019 10 08.
Artículo en Inglés | MEDLINE | ID: mdl-31564646

RESUMEN

Cellular responses to transforming growth factor ß (TGF-ß) depend on cell context. Here, we explored how TGF-ß/nodal signaling crosstalks with the epigenome to promote mesendodermal differentiation. We find that expression of a group of mesendodermal genes depends on both TRIM33 and nodal signaling in embryoid bodies (EBs) but not in embryonic stem cells (ESCs). Only in EBs, TRIM33 binds these genes in the presence of expanded H3K18ac marks. Furthermore, the H3K18ac landscape at mesendodermal genes promotes TRIM33 recruitment. We reveal that HDAC1 binds to active gene promoters and interferes with TRIM33 recruitment to mesendodermal gene promoters. However, the TRIM33-interacting protein p300 deposits H3K18ac and further enhances TRIM33 recruitment. ATAC-seq data demonstrate that TRIM33 primes mesendodermal genes for activation by maintaining chromatin accessibility at their regulatory regions. Altogether, our study suggests that HDAC1 and p300 are key factors linking the epigenome through TRIM33 to the cell context-dependent nodal response during mesendodermal differentiation.


Asunto(s)
Diferenciación Celular , Histonas/metabolismo , Mesodermo/citología , Mesodermo/metabolismo , Proteína Nodal/metabolismo , Transducción de Señal , Acetilación , Diferenciación Celular/genética , Cromatina/genética , Cromatina/metabolismo , Células Madre Embrionarias/citología , Células Madre Embrionarias/metabolismo , Regulación del Desarrollo de la Expresión Génica , Humanos , Regiones Promotoras Genéticas , Unión Proteica , Transporte de Proteínas , Proteína Smad2/metabolismo , Proteína smad3/metabolismo , Factores de Transcripción/metabolismo , Factores de Transcripción p300-CBP/metabolismo
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