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Donor T-cell DNMT3a regulates alloreactivity in murine models of hematopoietic stem cell transplantation [RNA-seq]

ABSTRACT: Donor T-cell RNA expression state has an effect on alloreactivity. We applied RNA-Seq and the Deseq2 analysis pipeline to investigate the role of gene expression in mice receiving transplantation from T-cell conditional DNMT3a KO donors.

ORGANISM(S): Mus musculus

PROVIDER: GSE196540 | GEO | 2022/06/13

REPOSITORIES: GEO

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Donor T-cell DNMT3a regulates alloreactivity in murine models of hematopoietic stem cell transplantation [WGBS]

Project description:Donor T-cell methylation state has an effect on alloreactivity. We applied WGBS and the InformME analysis pipeline to investigate the role of DNA methylation in mice receiving transplantation from T-cell conditional DNMT3a KO donors.

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Donor T-cell DNMT3a regulates alloreactivity in murine models of hematopoietic stem cell transplantation.

Project description:Donor T-cell DNMT3a regulates alloreactivity in murine models of hematopoietic stem cell transplantation.

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Donor T-cell DNMT3a regulates alloreactivity in murine models of hematopoietic stem cell transplantation [WGBS]

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Donor T-cell DNMT3a regulates alloreactivity in murine models of hematopoietic stem cell transplantation [RNA-seq]

Project description:Donor T-cell DNMT3a regulates alloreactivity in murine models of hematopoietic stem cell transplantation [RNA-seq]

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Donor T cell DNMT3a regulates alloreactivity in mouse models of hematopoietic stem cell transplantation.

Project description:DNA methyltransferase 3a (DNMT3a) is an important part of the epigenetic machinery that stabilizes patterns of activated T cell responses. We hypothesized that donor T cell DNMT3a regulates alloreactivity after allogeneic blood and marrow transplantation (allo-BMT). T cell conditional Dnmt3a KO mice were used as donors in allo-BMT models. Mice receiving allo-BMT from KO donors developed severe acute graft-versus-host disease (aGVHD), with increases in inflammatory cytokine levels and organ histopathology scores. KO T cells migrated and proliferated in secondary lymphoid organs earlier and demonstrated an advantage in trafficking to the small intestine. Donor T cell subsets were purified after BMT for whole-genome bisulfite sequencing (WGBS) and RNA-Seq. KO T cells had global methylation similar to that of WT cells, with distinct, localized areas of hypomethylation. Using a highly sensitive computational method, we produced a comprehensive profile of the altered epigenome landscape. Hypomethylation corresponded with changes in gene expression in several pathways of T cell signaling and differentiation. Additionally, Dnmt3a-KO T cells resulted in superior graft-versus-tumor activity. Our findings demonstrate a critical role for DNMT3a in regulating T cell alloreactivity and reveal pathways that control T cell tolerance. These results also provide a platform for deciphering clinical data that associate donor DNMT3a mutations with increased GVHD, decreased relapse, and improved survival.

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Donor T-cell DNMT3a regulates alloreactivity in murine models of hematopoietic stem cell transplantation.

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