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

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

PROVIDER: PRJNA805295 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR17979045_1.fastq.gz	Fastqsanger.gz
	SRR17979045_2.fastq.gz	Fastqsanger.gz
	SRR17979046_1.fastq.gz	Fastqsanger.gz
	SRR17979046_2.fastq.gz	Fastqsanger.gz
	SRR17979047_1.fastq.gz	Fastqsanger.gz

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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.

2022-06-13 | GSE196541 | GEO

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

Project description: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.

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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 [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.

| S-EPMC9246380 | biostudies-literature

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

Project description:This SuperSeries is composed of the SubSeries listed below.

2022-06-13 | GSE196542 | GEO

RNASeq of K562 cell clones for DNMT3A-WT, DNMT3A-W305*, DNMT3A-R882H, DNMT3A-R882C

Project description:Donor blood saves lives, yet the potential impact of recurrent large-volume phlebotomy on donor health and hematopoietic stem cells (HSCs) remains largely unexplored. In our study, we conducted a comprehensive screening of 217 older male volunteer donors with a history of extensive blood donation (>100 life-time donations) to investigate the phenomenon of clonal hematopoiesis (CH). No significant difference in the overall incidence of CH was found in frequent donors (FD) compared to sporadic donors (<10 life-time donations, 212 donors). However, upon deeper analysis of mutations in DNMT3A, the most commonly affected gene in CH, we observed distinct mutational patterns between the FD and age/sex matched control donor (CD) cohorts. Functional analysis of FD enriched DNMT3A variants examined in CRISPR-edited human HSCs demonstrated their competitive outgrowth potential upon stimulation with erythropoietin (EPO), a hormone which increases in response to blood loss. In contrast, clones harboring leukemogenic DNMT3A R882 mutations increase upon stimulation with IFNy. Through concurrent mutational and immunophenotypic profiling of primary samples at single cell resolution, a myeloid bias of premalignant R882 mutant HSCs was found, while no significant lineage bias was observed in HSCs harboring EPO responsive DNMT3A variants. The latter exhibited preferential erythroid differentiation when persistent erythropoietic stress was applied to CRISPR-edited human HSC xenografts. Our data demonstrate a nuanced ongoing Darwinian evolution at the somatic stem cell level, with EPO identified as a novel environmental factor that favors HSCs carrying certain DNMT3A mutations.

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DNMT3A-dependent DNA methylation shapes the endothelial enhancer landscape [WGBS]

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Donor T-cell alloreactivity against host thymic epithelium limits T-cell development after bone marrow transplantation.

Project description:Acute graft-versus-host disease (aGVHD) impairs thymus-dependent T-cell regeneration in recipients of allogeneic bone marrow transplants through yet to be defined mechanisms. Here, we demonstrate in mice that MHC-mismatched donor T cells home into the thymus of unconditioned recipients. There, activated donor T cells secrete IFN-gamma, which in turn stimulates the programmed cell death of thymic epithelial cells (TECs). Because TECs themselves are competent and sufficient to prime naive allospecific T cells and to elicit their effector function, the elimination of host-type professional antigen-presenting cells (APCs) does not prevent donor T-cell activation and TEC apoptosis, thus precluding normal thymopoiesis in transplant recipients. Hence, strategies that protect TECs may be necessary to improve immune reconstitution following allogeneic bone marrow transplantation.

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DNMT3A-dependent DNA methylation shapes the endothelial enhancer landscape [WGBS II]

Project description:DNMT3A-dependent DNA methylation shapes the endothelial enhancer landscape [WGBS II]

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