Browsing by Subject "SWI/SNF"

Now showing 1 - 2 of 2
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    Genome-wide studies reveal the essential and opposite roles of ARID1A in controlling human cardiogenesis and neurogenesis from pluripotent stem cells
    (BMC, 2020-07-09) Liu, Juli; Liu, Sheng; Gao, Hongyu; Han, Lei; Chu, Xiaona; Sheng, Yi; Shou, Weinian; Wang, Yue; Liu, Yunlong; Wan, Jun; Yang, Lei; BioHealth Informatics, School of Informatics and Computing
    Background Early human heart and brain development simultaneously occur during embryogenesis. Notably, in human newborns, congenital heart defects strongly associate with neurodevelopmental abnormalities, suggesting a common gene or complex underlying both cardiogenesis and neurogenesis. However, due to lack of in vivo studies, the molecular mechanisms that govern both early human heart and brain development remain elusive. Results Here, we report ARID1A, a DNA-binding subunit of the SWI/SNF epigenetic complex, controls both neurogenesis and cardiogenesis from human embryonic stem cells (hESCs) through distinct mechanisms. Knockout-of-ARID1A (ARID1A−/−) leads to spontaneous differentiation of neural cells together with globally enhanced expression of neurogenic genes in undifferentiated hESCs. Additionally, when compared with WT hESCs, cardiac differentiation from ARID1A −/− hESCs is prominently suppressed, whereas neural differentiation is significantly promoted. Whole genome-wide scRNA-seq, ATAC-seq, and ChIP-seq analyses reveal that ARID1A is required to open chromatin accessibility on promoters of essential cardiogenic genes, and temporally associated with key cardiogenic transcriptional factors T and MEF2C during early cardiac development. However, during early neural development, transcription of most essential neurogenic genes is dependent on ARID1A, which can interact with a known neural restrictive silencer factor REST/NRSF. Conclusions We uncover the opposite roles by ARID1A to govern both early cardiac and neural development from pluripotent stem cells. Global chromatin accessibility on cardiogenic genes is dependent on ARID1A, whereas transcriptional activity of neurogenic genes is under control by ARID1A, possibly through ARID1A-REST/NRSF interaction.
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    Stepwise activities of mSWI/SNF family chromatin remodeling complexes direct T cell activation and exhaustion
    (Elsevier, 2023) Battistello, Elena; Hixon, Kimberlee A.; Comstock, Dawn E.; Collings, Clayton K.; Chen, Xufeng; Rodriguez Hernaez, Javier; Lee, Soobeom; Cervantes, Kasey S.; Hinkley, Madeline M.; Ntatsoulis, Konstantinos; Cesarano, Annamaria; Hockemeyer, Kathryn; Haining, W. Nicholas; Witkowski, Matthew T.; Qi, Jun; Tsirigos, Aristotelis; Perna, Fabiana; Aifantis, Iannis; Kadoch, Cigall; Medicine, School of Medicine
    Highly coordinated changes in gene expression underlie T cell activation and exhaustion. However, the mechanisms by which such programs are regulated and how these may be targeted for therapeutic benefit remain poorly understood. Here, we comprehensively profile the genomic occupancy of mSWI/SNF chromatin remodeling complexes throughout acute and chronic T cell stimulation, finding that stepwise changes in localization over transcription factor binding sites direct site-specific chromatin accessibility and gene activation leading to distinct phenotypes. Notably, perturbation of mSWI/SNF complexes using genetic and clinically relevant chemical strategies enhances the persistence of T cells with attenuated exhaustion hallmarks and increased memory features in vitro and in vivo. Finally, pharmacologic mSWI/SNF inhibition improves CAR-T expansion and results in improved anti-tumor control in vivo. These findings reveal the central role of mSWI/SNF complexes in the coordination of T cell activation and exhaustion and nominate small-molecule-based strategies for the improvement of current immunotherapy protocols.