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Deleting DNMT3A in CAR T cells prevents exhaustion and 1 enhances antitumor activity

ABSTRACT: Whole-genome bisulfite sequencing data generated from WT and DNMT3A KO or IL-10 KO CAR T cells. These data were generate at early (week 1) and later (week 4) time points during in vitro serial stimulation of the CAR T cells, or after infusion into tumor bearing mice. These data document the DNA methylation changes that are coupled to the functional decline in CAR T cells during their sustained stimulation, and the causal nature of DNMT3A-specific methylation in mediating the functional impairment of the CAR T cells.

ORGANISM(S): Homo sapiens

PROVIDER: GSE184568 | GEO | 2021/11/22

REPOSITORIES: GEO

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Deleting DNMT3A in CAR T cells prevents exhaustion and 1 enhances antitumor activity

Project description:Deleting DNMT3A in CAR T cells prevents exhaustion and 1 enhances antitumor activity

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de novo DNA Methylation Balances Hematopoietic Stem Cell Self-Renewal and Differentiation

Project description:Cytosine methylation is an epigenetic mark usually associated with gene repression. Despite a requirement for de novo DNA methylation for differentiation of embryonic stem cells, its role in somatic stem cells is unknown. Using conditional ablation, we show that loss of either, or both, Dnmt3a or Dnmt3b, progressively impedes hematopoietic stem cell (HSC) differentiation during serial in vivo passage. Concomitantly, HSC self-renewal is immensely augmented in absence of either Dnmt3, particularly Dnmt3a. Dnmt3-KO HSCs show upregulation of HSC multipotency genes and downregulation of early differentiation factors, and the differentiated progeny of Dnmt3-KO HSCs exhibit hypomethylation and incomplete repression of HSC-specific genes. HSCs lacking Dnmt3a manifest hyper-methylation of CpG islands and hypo-methylation of genes which are highly correlated with human hematologic malignancies. These data establish that aberrant DNA methylation has direct pathologic consequences for somatic stem cell development, leading to inefficient differentiation and maintenance of a self-renewal program. Reduced representation bisulfite sequencing (MspI,~40-220bp size fraction) of secondarily-transplanted wild-type and Dnmt3a conditional knockout hematopoietic stem cells. We used microarrays to detail the global expression of genes in secondarily-transplanted control-HSCs and Dnmt3a-KO-HSCs.

2011-09-30 | E-GEOD-27322 | biostudies-arrayexpress

Genome-wide maps of chromatin state and RNA-seq in WT and Dnmt3a KO BMDMs (bone marrow derived macrophages) [RRBS, ATAC-seq, CHIP-seq]

Project description:To identify soluble factors released from Dnmt3a KO macrophages that might drive differences in osteoclast differentiation, we performed RNA sequencing on unstimulated BMDMs from WT and Dnmt3a KO mice. To investigate the mechanistic basis for the inflammatory phenotype. of myeloid cells with loss of Dnmt3a,we performed reduced representation bisulfite sequencing (RRBS) on Dnmt3a KO and WT BMDMs to assess methylation changes. Concurrently, we performed ATAC-sequencing (ATAC-seq) to assess differences in chromatin accessibility between WT and Dnmt3a KO BMDMs in the context of changes in methylation. We performed chromatin immunoprecipitation sequencing (CHIP-seq) for Irf3 and Rela based on ATAC-seq analysis.

2021-10-07 | GSE184443 | GEO

Genome-wide maps of chromatin state and RNA-seq in WT and Dnmt3a KO BMDMs (bone marrow derived macrophages) [RNA-seq]

2021-10-07 | GSE183480 | GEO

Genome-wide identification of distinct target loci for de novo DNA methylation by DNMT3A and DNMT3B during mammalian development

Project description:DNA methylation plays essential roles in mammalian development. During post-implantation development, de novo establishment of DNA methylation is accomplished by DNA methyltransferases, in particular DNMT3A and DNMT3B. At present, the distinct functions of these two enzymes remain largely elusive. To comprehensively identify the target sites for de novo DNA methylation by the DNMT3 enzymes, we took advantage of female mouse ES cells established in the presence of MEK and Gsk3 inhibitors, which lack most DNA methylation (2i/L ES cells), in combination with genetic ablation of Dnmt3a or Dnmt3b. We analyzed de novo DNA methylation in mouse embryonic fibroblasts (2i-MEFs) derived from Dnmt3 knockout (KO) 2i/L ES cells. Both Dnmt3a and Dnmt3b KO 2i-MEFs exhibited a modest but global reduction in CpG methylation, which was particularly notable on the X chromosome in Dnmt3b KO cells. Although most genes were methylated similarly in both knockouts, we identified 355 and 333 uniquely unmethylated genes in Dnmt3a and Dnmt3b KO 2i-MEFs, respectively. Notably, Dnmt3a was exclusively required for de novo methylation at both TSS regions and gene bodies of Polycomb group (PcG) target developmental genes. Consistent with this, tissue-specific DNA methylation at PcG target developmental genes was substantially reduced in Dnmt3a KO embryos. Finally, we found that human patients with DNMT3A mutant acute myeloid leukemia (AML) or harboring DNMT3B mutation associated with immunodeficiency, centromere, and facial anomalies (ICF) syndrome exhibited reduced CpG methylation at regions that were hypomethylated in Dnmt3a or Dnmt3b KO 2i-MEFs, respectively. Collectively, our findings in DNA-hypomethylated 2i/L ES cells revealed a set of unique de novo DNA methylation target sites for both DNMT3 enzymes during mammalian development that overlap with hypomethylated sites in human patients.

2020-05-13 | GSE111172 | GEO

Genome-wide location analysis of Dnmt3a-mediated epigenetic regulation in murine postnatal subventricular zone (SVZ) neural stem cells (NSCs) [NimbleGen]

Project description:DNA methylation at proximal promoters facilitates lineage restriction by silencing cell-type specific genes. However, euchromatic DNA methylation frequently occurs in regions outside promoters. The functions of such non-proximal promoter DNA methylation are unclear. Here we show that the de novo DNA methyltransferase Dnmt3a is expressed in postnatal neural stem cells (NSCs) and is required for neurogenesis. Genome-wide analysis of postnatal NSCs indicates that Dnmt3a occupies and methylates intergenic regions and gene bodies flanking proximal promoters of a large cohort of transcriptionally permissive genes, many of which encode regulators of neurogenesis. Surprisingly, Dnmt3a-dependent non-proximal promoter methylation promotes expression of these neurogenic genes by functionally antagonizing Polycomb repression. Thus, non-promoter DNA methylation by Dnmt3a may be utilized for maintaining active chromatin states of genes critical for development. Chromatin extracted from wild-type (WT) or Dnmt3a-null (KO) SVZ NSCs was immunoprecipitated with indicated antibodies and analyzed by NimbleGen 2.1M mouse whole genome tiling microarrays (a 4-array set covering the entired non-repetitive portion of mouse genome). Whole cell extract (WCE) was used as input controls for IP/WCe experiments. For IP/IP experiments, immunoprecipitated DNA from WT and KO NSCs was directly compared on the same microarrays. For identifying Dnmt3a-dependent DNA methylation at a genome-wide scale, a dye-swap design was employed for comparing DNA methylation levels between WT and KO SVZ NSCs.

2010-06-25 | E-GEOD-22475 | biostudies-arrayexpress

Role of de novo DNA methyltransferases in hematopoietic stem cells (WGBS)

Project description:To investigate the global DNA methylation changes in Dnmt3a-KO and Dnmt3ab-dKO HSCs compared to control HSCs, we performed whole genome bisulfite sequencing Mouse hematopoietic stem cell DNA methylation profiles of control, Dnmt3a-KO and Dnmt3ab-dKO HSCs were generated generated by deep sequencing, in duplicate, using Illumina Hiseq 2000

2014-08-19 | E-GEOD-50780 | biostudies-arrayexpress

Reduced representative bisulfite sequencing (RRBS) analysis for a genome-wide comparison of DNA methylation in wild-type, USP7-KO-1, DNMT3A/3B-DKO and DNMT3A/DNMT3B/USP7-TKO HeLa cell lines.

Project description:To better characterize the effects of USP7 on DNA methylation, we performed reduced representative bisulfite sequencing (RRBS) analysis for a genome-wide comparison of DNA methylation in wild-type, USP7-KO-1, DNMT3A/3B-DKO and DNMT3A/DNMT3B/USP7-TKO HeLa cell lines. RRBS analysis showed increased DNA methylation in USK7-KO cells and loss of USP7 elevates DNA methylation on pre-existing sites and de novo methylation.

2020-09-07 | GSE136159 | GEO

Gene expression and DNA methylation of lung tumors in Dnmt3a deficient vs. WT mice

Project description:This SuperSeries is composed of the following subset Series: GSE32415: Mouse lung tumor tissue: Dnmt3a KO vs. Dnmt3a WT GSE32484: DNA methylation of dnmt3a deficient Kras lung tumors and dnmt3a wt Kras lung tumors Refer to individual Series

2011-10-25 | E-GEOD-32487 | biostudies-arrayexpress

Microarray analysis of satellite cells in Dnmt3a knockout mice

Project description:DNA methylation occurs as 5-methylcytosines mainly at cytosine-guanine dinucleotides, so-called CpG sites, and such methylation is a well-studied epigenetic mechanism for transcriptional regulation. Generally, DNA methylation of the gene promoter is correlated with transcriptional repression. Genomic DNA methylation patterns are established by the actions of the de novo methyltransferases Dnmt3a and Dnmt3b, and are maintained by the methyltransferase Dnmt1. Expression of Dnmt3a mRNA is relatively high in skeletal muscle, suggesting a major role in transcriptional regulation. Also, denervation of skeletal muscle decreased expression of Dnmt3a mRNA, suggesting involvement of Dnmt3a in pathophysiology during atrophy. Decreased regeneration capacity in atrophied skeletal muscle hampers muscle mass recovery after injury and the impaired muscle function, lowers the quality of life. We found that in skeletal muscle of atrophy models, Dnmt3a was decreased. Muscle regeneration was delayed in the skeletal muscle-specific Dnmt3a knockout (Dnmt3a-KO) mice, in which Dnmt3a was deleted in skeletal muscle as well as in satellite cells, important for muscle regeneration. In this study, we used Dnmt3a-KO mice, and attempt to clarify the mechanism of reduced muscle regeneration during atrophy. The microarray data shows that expression of a Gdf/Bmp family protein Gdf5, which suppressed differentiation of satellite cells, is activated in Dnmt3a-KO mice compared with wild-type mice.

2019-04-01 | GSE97340 | GEO

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