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1.
Mol Cell ; 83(8): 1350-1367.e7, 2023 04 20.
Artículo en Inglés | MEDLINE | ID: mdl-37028419

RESUMEN

The mammalian SWI/SNF (mSWI/SNF or BAF) family of chromatin remodeling complexes play critical roles in regulating DNA accessibility and gene expression. The three final-form subcomplexes-cBAF, PBAF, and ncBAF-are distinct in biochemical componentry, chromatin targeting, and roles in disease; however, the contributions of their constituent subunits to gene expression remain incompletely defined. Here, we performed Perturb-seq-based CRISPR-Cas9 knockout screens targeting mSWI/SNF subunits individually and in select combinations, followed by single-cell RNA-seq and SHARE-seq. We uncovered complex-, module-, and subunit-specific contributions to distinct regulatory networks and defined paralog subunit relationships and shifted subcomplex functions upon perturbations. Synergistic, intra-complex genetic interactions between subunits reveal functional redundancy and modularity. Importantly, single-cell subunit perturbation signatures mapped across bulk primary human tumor expression profiles both mirror and predict cBAF loss-of-function status in cancer. Our findings highlight the utility of Perturb-seq to dissect disease-relevant gene regulatory impacts of heterogeneous, multi-component master regulatory complexes.


Asunto(s)
Ensamble y Desensamble de Cromatina , Neoplasias , Animales , Humanos , Proteínas Cromosómicas no Histona/genética , Proteínas Cromosómicas no Histona/metabolismo , Factores de Transcripción/genética , Factores de Transcripción/metabolismo , Cromatina/genética , Mamíferos/metabolismo
2.
Immunometabolism ; 3(1)2021.
Artículo en Inglés | MEDLINE | ID: mdl-33604081

RESUMEN

Akt kinases translate various external cues into intracellular signals that control cell survival, proliferation, metabolism and differentiation. This review discusses the requirement for Akt and its targets in determining the fate and function of T cells. We discuss the importance of Akt at various stages of T cell development including ß-selection during which Akt fulfills the energy requirements of highly proliferative DN3 cells. Akt also plays an integral role in CD8 T cell biology where its regulation of Foxo transcription factors and mTORC1 metabolic activity controls effector versus memory CD8 T cell differentiation. Finally, Akt promotes the differentiation of naïve CD4 T cells into Th1, Th17 and Tfh cells but inhibits the development of Treg cells. We also highlight how modulating Akt in T cells is a promising avenue for enhancing cell-based cancer immunotherapy.

4.
Nat Struct Mol Biol ; 27(9): 836-845, 2020 09.
Artículo en Inglés | MEDLINE | ID: mdl-32747783

RESUMEN

Interactions between chromatin-associated proteins and the histone landscape play major roles in dictating genome topology and gene expression. Cancer-specific fusion oncoproteins, which display unique chromatin localization patterns, often lack classical DNA-binding domains, presenting challenges in identifying mechanisms governing their site-specific chromatin targeting and function. Here we identify a minimal region of the human SS18-SSX fusion oncoprotein (the hallmark driver of synovial sarcoma) that mediates a direct interaction between the mSWI/SNF complex and the nucleosome acidic patch. This binding results in altered mSWI/SNF composition and nucleosome engagement, driving cancer-specific mSWI/SNF complex targeting and gene expression. Furthermore, the C-terminal region of SSX confers preferential affinity to repressed, H2AK119Ub-marked nucleosomes, underlying the selective targeting to polycomb-marked genomic regions and synovial sarcoma-specific dependency on PRC1 function. Together, our results describe a functional interplay between a key nucleosome binding hub and a histone modification that underlies the disease-specific recruitment of a major chromatin remodeling complex.


Asunto(s)
Proteínas Cromosómicas no Histona/metabolismo , Histonas/metabolismo , Proteínas de Neoplasias/metabolismo , Proteínas de Fusión Oncogénica/metabolismo , Proteínas Proto-Oncogénicas/metabolismo , Proteínas Represoras/metabolismo , Sarcoma Sinovial/metabolismo , Factores de Transcripción/metabolismo , Ubiquitinas/metabolismo , Línea Celular Tumoral , Proteínas Cromosómicas no Histona/química , Células HEK293 , Humanos , Modelos Moleculares , Proteínas de Neoplasias/química , Nucleosomas/metabolismo , Nucleosomas/patología , Proteínas de Fusión Oncogénica/química , Conformación Proteica , Proteínas Proto-Oncogénicas/química , Proteínas Represoras/química , Sarcoma Sinovial/patología , Factores de Transcripción/química , Ubiquitinación
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