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• Coordinated regulation of glycolysis, mitochondrial oxidative phosphorylation, and fatty acid oxidation provides the necessary energy to maintain long-term (LT) stem cell properties during ex vivo reprogramming of human CD34+ cells. • Ex vivo reprogramming leads to the acquisition and maintenance of LT-hematopoietic stem cell (HSC) transcriptomic and phenotype profiles. • SIRT1 and SIRT3 are required to maintain the functional capacity of HSCs during reprogramming. The regenerative potential of human hematopoietic stem cells (HSCs) is functionally defined by their ability to provide life-long blood cell production and to repopulate myeloablated allogeneic transplant recipients. The expansion of HSC numbers is dependent not only on HSC divisions but also on a coordinated adaptation of HSCs to metabolic stress. These variables are especially critical during the ex vivo culture of HSCs with cytokine combinations, which frequently results in HSC exhaustion. We have previously reported that human CD34+ hematopoietic stem and progenitor cells (HSPCs) can be efficiently reprogrammed ex vivo and that the number of phenotypic HSCs with long-term repopulation capacity is expanded in the presence of a combination of cytokines and an epigenetic modifier. Here, we present evidence that ex vivo HSC reprogramming and maintenance is accompanied by increased transcripts of genes regulating metabolic integrity, including SIRT1 and SIRT3. [ABSTRACT FROM AUTHOR]

ARID2 is the most recurrently mutated SWI/SNF complex member in melanoma; however, its tumor-suppressive mechanisms in the context of the chromatin landscape remain to be elucidated. Here, we model ARID2 deficiency in melanoma cells, which results in defective PBAF complex assembly with a concomitant genomic redistribution of the BAF complex. Upon ARID2 depletion, a subset of PBAF and shared BAF-PBAF-occupied regions displays diminished chromatin accessibility and associated gene expression, while BAF-occupied enhancers gain chromatin accessibility and expression of genes linked to the process of invasion. As a function of altered accessibility, the genomic occupancy of melanoma-relevant transcription factors is affected and significantly correlates with the observed transcriptional changes. We further demonstrate that ARID2-deficient cells acquire the ability to colonize distal organs in multiple animal models. Taken together, our results reveal a role for ARID2 in mediating BAF and PBAF subcomplex chromatin dynamics with consequences for melanoma metastasis. [Display omitted] • ARID2 loss results in impaired PBAF complex assembly and BAF genomic redistribution • Altered SWI/SNF dynamics results in chromatin accessibility and TF binding changes • PBAF loss drives an invasive gene expression signature and phenotype in melanoma The tumor-suppressive functions of the SWI/SNF subunit ARID2 remain ill-defined in the context of melanoma. Carcamo et al. demonstrate that, upon ARID2 depletion, the PBAF complex fails to assemble, altering BAF genomic occupancy with consequences on chromatin accessibility, transcription factor binding, and transcriptional changes that promote metastasis. [ABSTRACT FROM AUTHOR]

The pattern of genetic alterations in cancer driver genes in patients with hepatocellular carcinoma (HCC) is highly diverse, which partially explains the low efficacy of available therapies. In spite of this, the existing mouse models only recapitulate a small portion of HCC inter-tumor heterogeneity, limiting the understanding of the disease and the nomination of personalized therapies. Here, we aimed at establishing a novel collection of HCC mouse models that captured human HCC diversity. By performing hydrodynamic tail-vein injections, we tested the impact of altering a well-established HCC oncogene (either MYC or β-catenin) in combination with an additional alteration in one of eleven other genes frequently mutated in HCC. Of the 23 unique pairs of genetic alterations that we interrogated, 9 were able to induce HCC. The established HCC mouse models were characterized at histopathological, immune, and transcriptomic level to identify the unique features of each model. Murine HCC cell lines were generated from each tumor model, characterized transcriptionally, and used to identify specific therapies that were validated in vivo. Cooperation between pairs of driver genes produced HCCs with diverse histopathology, immune microenvironments, transcriptomes, and drug responses. Interestingly, MYC expression levels strongly influenced β-catenin activity, indicating that inter-tumor heterogeneity emerges not only from specific combinations of genetic alterations but also from the acquisition of expression-dependent phenotypes. This novel collection of murine HCC models and corresponding cell lines establishes the role of driver genes in diverse contexts and enables mechanistic and translational studies. [ABSTRACT FROM AUTHOR]