Browsing by Author "Tsirigos, Aristotelis"

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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.
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    The common murine retroviral integration site activating Hhex marks a distal regulatory enhancer co-opted in human early T-cell precursor leukemia
    (American Society for Biochemistry and Molecular Biology, 2025) Hardwick, Joyce; Rodriguez-Hernaez, Javier; Gambi, Giovanni; Venters, Bryan J.; Guo, Yan; Li, Liqi; Love, Paul E.; Copeland, Neal G.; Jenkins, Nancy A.; Papaioannou, Dimitrios; Aifantis, Iannis; Tsirigos, Aristotelis; Ivan, Mircea; Davé, Utpal P.; Medicine, School of Medicine
    The Hhex gene encodes a transcription factor that is important for both embryonic and post-natal development, especially of hematopoietic tissues. Hhex is one of the most common sites of retroviral integration in mouse models. We found the most common integrations in AKXD (recombinant inbred strains) T-ALLs occur 57-61kb 3′ of Hhex and activate Hhex gene expression. The genomic region of murine leukemia virus (MLV) integrations has features of a developmental stage-specific cis regulatory element (CRE), as evidenced by ATAC-seq in murine progenitor cells and high H3K27 acetylation at the syntenic CRE in human hematopoietic cell lines. With ChIP-exonuclease, we describe occupancy of LIM domain binding protein 1 (LDB1), the constitutive partner of the LIM Only-2 (LMO2), GATA1, and TAL1 transcription factors at GATA sites and at a composite GATA-E box within the CRE. With virtual 4C analysis, we observed looping between this +65kb CRE and the proximal intron one enhancer of HHEX in primary human ETP-ALLs and in normal progenitor cells. Our results show that retroviral integrations at intergenic sites can mark and take advantage of CREs. Specifically, in the case of HHEX activation, this newly described +65kb CRE is co-opted in the pathogenesis of ETP-ALL by the LMO2/LDB1 complex.