Targeting EHMT2 Enhances NK Cell Maturation and Antitumor Activity [CUT&Tag]
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE325754 | GEO | 2026/07/20
REPOSITORIES: GEO
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Project description:Integrated RNA-seq and H3K9me2 CUT&Tag profiling reveal that Ehmt2 loss reduces the repressive histone mark H3K9me2 and derepresses transcriptional programs associated with NK cell differentiation and cytotoxicity.
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Project description:Mouse embryonic stem cells (mESCs) and other naïve pluripotent stem cells, under specific conditions, can reverse typical developmental trajectories and de-differentiate into 2-cell-like cells (2CLCs) that resemble the mammalian embryo during zygotic genome activation (ZGA). We implemented a multipurpose allele for acute protein depletion and efficient immunoprecipitation to dissect the molecular functions of EHMT2 in mESCs. This approach allowed us to define different types of EHMT2 target genes and distinct modes of chromatin engagement and repression. Most notably, EHMT2 directly represses large clusters of co-regulated gene loci that comprise a significant fraction of the 2CLC-specific transcriptome by initiating H3K9me2 spreading from distal LINE-1 elements. Conversely, the loss of EHMT2 allows the recruitment of the activator DPPA2/4 to promoter-proximal ERVs in 2CLCs, thus facilitating the mESC-to-2CLC transition. Repression of germ layer-associated transcripts by EHMT2 occurs outside of gene clusters in collaboration with ZFP462 and entails binding to non-repeat enhancers. Our data suggests that EHMT2 functions as an attenuator of the bidirectional differentiation potential of mouse naïve pluripotent stem cells and define molecular models for the gene-specific repressive activity of this essential histone methyltransferase.
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Project description:Oligodendrocyte progenitor cells (OPCs) represent a population of electrically active and dividing cells, which are capable of responding to neuronal activity, by proliferating and differentiating. Here we report that the repressive euchromatic H3K9me2 histone mark, deposited by the histone mehyltransferases EHMT1 and EHMT2 enzymes, increases in proliferating OPCs in mice following optogenetic stimulation of neuronal activity. Using primary cultured OPCs with genetic deletion of Ehmt1 and Ehmt2, and pharmacological inhibition of EHMT enzymatic activity, we reveal the importance of these enzymes in repressing the expression of genes regulating cell death and electrical properties in proliferating OPCs. Consistent with these findings, we detect higher levels of cholinergic muscarinic receptors, fewer numbers of oligodendrocyte lineage cells and lower levels of the myelin basic protein (MBP) in mice with lineage specific ablation of Ehmt1 and Ehmt2. Together these data suggest that the repressive H3K9me2 histone mark, whose levels increase in proliferating OPCs after neuronal stimulation, is an important modulator of cell death and proteins regulating the electrical properties of OPCs.
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Project description:Mouse embryonic stem cells (mESCs) and other naïve pluripotent stem cells, under specific conditions, can reverse typical developmental trajectories and de-differentiate into 2-cell-like cells (2CLCs) that resemble the mammalian embryo during zygotic genome activation (ZGA). We implemented a multipurpose allele for acute protein depletion and efficient immunoprecipitation to dissect the molecular functions of EHMT2 in mESCs. This approach allowed us to define different types of EHMT2 target genes and distinct modes of chromatin engagement and repression. Most notably, EHMT2 directly represses large clusters of co-regulated gene loci that comprise a significant fraction of the 2CLC-specific transcriptome by initiating H3K9me2 spreading from distal LINE-1 elements. Conversely, the loss of EHMT2 allows the recruitment of the activator DPPA2/4 to promoter-proximal ERVs in 2CLCs, thus facilitating the mESC-to-2CLC transition. Repression of germ layer-associated transcripts by EHMT2 occurs outside of gene clusters in collaboration with ZFP462 and entails binding to non-repeat enhancers. Our data suggests that EHMT2 functions as an attenuator of the bidirectional differentiation potential of mouse naïve pluripotent stem cells and define molecular models for the gene-specific repressive activity of this essential histone methyltransferase.
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Project description:Mouse embryonic stem cells (mESCs) and other naïve pluripotent stem cells, under specific conditions, can reverse typical developmental trajectories and de-differentiate into 2-cell-like cells (2CLCs) that resemble the mammalian embryo during zygotic genome activation (ZGA). We implemented a multipurpose allele for acute protein depletion and efficient immunoprecipitation to dissect the molecular functions of EHMT2 in mESCs. This approach allowed us to define different types of EHMT2 target genes and distinct modes of chromatin engagement and repression. Most notably, EHMT2 directly represses large clusters of co-regulated gene loci that comprise a significant fraction of the 2CLC-specific transcriptome by initiating H3K9me2 spreading from distal LINE-1 elements. Conversely, the loss of EHMT2 allows the recruitment of the activator DPPA2/4 to promoter-proximal ERVs in 2CLCs, thus facilitating the mESC-to-2CLC transition. Repression of germ layer-associated transcripts by EHMT2 occurs outside of gene clusters in collaboration with ZFP462 and entails binding to non-repeat enhancers. Our data suggests that EHMT2 functions as an attenuator of the bidirectional differentiation potential of mouse naïve pluripotent stem cells and define molecular models for the gene-specific repressive activity of this essential histone methyltransferase.
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