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

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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.

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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.

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