Abstract Achieving T cell tolerance ensures superior clinical outcomes in hematopoietic stem cell transplantation (HSCT). However, the in vivo T cell tolerance profiles in physiological state need to be further delineated. Here, we characterized the gene expression profile in tolerant T cells which was induced in healthy donors by granulocyte colony-stimulating factor, a stem cell mobilizer extensively used in HSCT. We identified suppressor of cytokine signaling 1 ( SOCS1 ) as an essential immune checkpoint for T cell tolerance in the mouse models and primary T cells in the HSCT context. Further spatial multiomics analysis characterized the distinct three-dimensional genome architecture and the gene regulatory network in tolerant T cells. We found STAT3 competes with CTCF and mediates the formation of a new chromatin loop between the SOCS1 promoter and upstream super enhancers during the induction of T cell tolerance. This study identifies SOCS1 as a key immune checkpoint and potential immune target for improving outcome of patients with HSCT.
An entry from the Cambridge Structural Database, the world’s repository for small molecule crystal structures. The entry contains experimental data from a crystal diffraction study. The deposited dataset for this entry is freely available from the CCDC and typically includes 3D coordinates, cell parameters, space group, experimental conditions and quality measures.
Summary Powdery mildew disease, elicited by the obligate fungal pathogen Blumeria graminis f.sp. tritici ( Bgt ), causes widespread yield losses in global wheat crop. However, the molecular mechanisms governing wheat defense to Bgt are still not well understood. Here we found that TuACO3 , encoding the 1‐aminocyclopropane‐1‐carboxylic acid (ACC) oxidase functioning in ethylene (ET) biosynthesis, was induced by Bgt infection of the einkorn wheat Triticum urartu , which was accompanied by increased ET content. Silencing TuACO3 decreased ET production and compromised wheat defense to Bgt , whereas both processes were enhanced in the transgenic wheat overexpressing TuACO3 . TuMYB46L, phylogenetically related to Arabidopsis MYB transcription factor AtMYB46, was found to bind to the TuACO3 promoter region in yeast‐one‐hybrid and EMSA experiments. TuMYB46L expression decreased rapidly following Bgt infection. Silencing TuMYB46L promoted ET content and Bgt defense, but the reverse was observed when TuMYB46L was overexpressed. Hence, decreased expression of TuMYB46L permits elevated function of TuACO3 in ET biosynthesis in Bgt ‐infected wheat. The TuMYB46L ‐ TuACO3 module regulates ET biosynthesis to promote einkorn wheat defense against Bgt . Furthermore, we found four chitinase genes acting downstream of the TuMYB46L ‐ TuACO3 module. Collectively, our data shed a new light on the molecular mechanisms underlying wheat defense to Bgt .
Abstract As approximately 70% of human breast tumors are estrogen receptor α (ERα)-positive, estrogen and ERα play essential roles in breast cancer development. By interrupting the ERα signaling pathway, endocrine therapy has been proven to be an effective therapeutic strategy. In this study, we identified a mechanism by which Transcription Start Site (TSS)-associated histone H3K27 acetylation signals the Super Elongation Complex (SEC) to regulate transcriptional elongation of the ESR1 (ERα) gene. SEC interacts with H3K27ac on ESR1 TSS through its scaffold protein AFF4. Depletion of AFF4 by siRNA or CRISPR/Cas9 dramatically reduces expression of ESR1 and its target genes, consequently inhibiting breast cancer cell growth. More importantly, a AFF4 mutant which lacks H3K27ac interaction failed to rescue ESR1 gene expression, suggesting H3K27 acetylation at TSS region is a key mark bridging the transition from transcriptional initiation to elongation, and perturbing SEC function can be an alternative strategy for targeting ERα signaling pathway at chromatin level.
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