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Division of labor among H3K4 Methyltransferases Define Distinct Facets of Homeostatic Plasticity

ABSTRACT: Division of labor among H3K4 Methyltransferases Define Distinct Facets of Homeostatic Plasticity

PROVIDER: PRJNA999349 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR25443000_1.fastq.gz	Fastqsanger.gz
	SRR25443000_2.fastq.gz	Fastqsanger.gz
	SRR25443001_1.fastq.gz	Fastqsanger.gz
	SRR25443001_2.fastq.gz	Fastqsanger.gz
	SRR25443002_1.fastq.gz	Fastqsanger.gz

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Division of labor among H3K4 Methyltransferases Define Distinct Facets of Homeostatic Plasticity

Project description:Histone H3 lysine 4 methylaton (H3K4me), a hallmark of transcriptionally engaged chromatin, is installed by the lysine methyltransferases 2 (KMT2) family of six enzymes in mammals. The six enzymes appear to have arisen from gene duplication of the ancient three enzymes found in the fruit fly. Heterozygous mutations in any of the six enzymes result in monogenic neurodevelopmental disorders, indicating nonredundant yet poorly understood roles of KMT2 family enzymes in neurodevelopment. Recent evidence suggests that histone methyltransferase activity may not be central to KMT2 functions; however, the enzymatic activity is evolutionary conserved, implicating the presence of selective pressure to maintain the catalytic activity. Here, we show that H3K4 methylation is dynamically regulated during prolonged alteration of neuronal activity. The perturbation of H3K4me by the H3.3K4M mutant blocks synaptic scaling, a form of homeostatic plasticity that buffers the impact of prolonged reductions or increases in network activity. Unexpectedly, we found that the six individual enzymes are all necessary for synaptic scaling and that the roles of KMT2 enzymes segregate into evolutionary-defined subfamilies; KMT2A and KMT2B (fly-Trx homologs) for synaptic downscaling, KMT2C and KMT2D (Trr homologs) for upscaling, and KMT2F and KMT2G (dSet homologs) for both directions. Selective blocking of KMT2A enzymatic activity by a small molecule and targeted disruption of the enzymatic domain both blocked the synaptic downscaling and interfered with the activity-dependent transcriptional program. Furthermore, our study revealed specific phases of synaptic downscaling, i.e., induction and maintenance, in which KMT2A and KMT2B play distinct roles. These results suggest that mammalian brains have co-opted intricate H3K4me installation to achieve stability of the expanding neuronal circuits.

2024-08-01 | GSE239471 | GEO

Comparative characterization of the seven H3K4 methyltransferases in Arabidopsis thaliana

Project description:Methylation of H3 lysine 4 (H3K4me) marks transcribed elements of eukaryotic genome, and their distribution alters dynamically through developmental stages and environmental change. These dynamic regulations are likely achieved by combinatorial work of H3K4me writers, which multi-cellular organisms carry multiple copies of. To better understand the chromatin targeting mechanisms of H3K4 methyltransferase in plants, here we comparatively characterized the seven H3K4 methyltransferases in model plants Arabidopsis. This work clarified, in combination with previous results, ATX1-5 (TRX/TRR-type methyltransferase) localizes on loci with specific sets of chromatin modifications and DNA motifs. Notably, ATX3 localizes to binding motifs of ASR3 and RAP2.11 transcriptional factors and also directly interacts with those TFs. ATXR7(SET1-type) and ATXR3 (non-canonical H3K4 methyltransferase) seemed co-transcriptional. Interestingly, ATXR3, the major H3K4me3 methyltransferase in Arabidopsis, was not associated with COMPASS, which suggests H3K4me3 regulation in plants and animals is divergent. Our work provides a foundation for understanding the regulation of H3K4 methyltransferases in plants.

2024-09-23 | GSE277439 | GEO

Acute depletion redefines the division of labor among DNA methyltransferases in methylating the human genome

Project description:Acute depletion redefines the division of labor among DNA methyltransferases in methylating the human genome

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Comparative characterization of the seven H3K4 methyltransferases in Arabidopsis thaliana

Project description:Comparative characterization of the seven H3K4 methyltransferases in Arabidopsis thaliana

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Acute depletion redefines the division of labor among DNA methyltransferases in methylating the human genome [methylation]

Project description:Global patterns of DNA methylation, mediated by the DNA methyltransferases (DNMTs), are disrupted in all cancers by mechanisms that remain largely unknown, hampering their development as therapeutic targets. Combinatorial acute depletion of all DNMTs in a pluripotent human tumor cell line, followed by epigenome and transcriptome analysis, revealed DNMT functions in unprecedented detail. DNMT3B occupancy regulates methylation during differentiation, while an unexpected interplay was discovered in which DNMT1 and DNMT3B antithetically regulate methylation and hydroxymethylation in gene bodies, a finding confirmed in other cell types. DNMT3B mediated nonCpG methylation, while DNMT3L influenced the activity of DNMT3B toward nonCpG versus CpG site methylation. Taken together, these data reveal new functional targets of each DNMT suggesting that isoform selective inhibition would be therapeutically advantageous. Overall, 27 samples were analyzed using the Infinium HumanMethylation450 BeadChip. 19 samples include NCCIT cells treated with various siRNAs targeting specific DNA methyltransferases. For the samples labeled biological replicate 1, NTC-1 serves as the control. Two additional biological replicates were analyzed for the siDNMT1, siDNMT3B, and si3B+3L condition; NTC-2 serves as the control for these samples. Six samples include HCT116 WT and various derivatives with alternative expression of DNMT1 and/or DNMT3B; WT serves as the control. Two samples include the undifferentiated (UD) and 7-day differentiated (DF) NCCIT cells; UD serves as the control.

2014-10-20 | E-GEOD-54840 | biostudies-arrayexpress

Catalytic-dependent and -independent functions of H3K4 methyltransferases in C. elegans development

Project description:Catalytic-dependent and -independent functions of H3K4 methyltransferases in C. elegans development

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Acute depletion redefines the division of labor among DNA methyltransferases in methylating the human genome [gene expression]

2014-10-20 | E-GEOD-54841 | biostudies-arrayexpress

Acute depletion redefines the division of labor among DNA methyltransferases in methylating the human genome [MBD-seq]

Project description:Global patterns of DNA methylation, mediated by the DNA methyltransferases (DNMTs), are disrupted in all cancers by mechanisms that remain largely unknown, hampering their development as therapeutic targets. Combinatorial acute depltion of all DNMTs in a pluripotent human tumor cell line, followed by epigenome and transcriptome analysis, revealed DNMT functions in unprecedented detail. DNMT3B occupancy regulates methylation during differentiation, while an unexpected interplay was discovered in which DNMT1 and DNMT3B antithetically regulate methylation and hydroxymethylation in gene bodies, a finding confirmed in other cell types. DNMT3B mediated nonCpG methylation, while DNMT3L influenced the activity of DNMT3B toward nonCpG versus CpG site methylation. Taken together, these data reveal new functional targets of each DNMT suggesting that isoform selective inhibition would be therapeutically advantageous. NCCIT cells were transfected with siRNAs against DNMT3B and a no-target control. Genomic DNA was extracted, and subsequently applied to affinity MBD-bound magnetic beads (Ribomed) to enrich methylated DNA sequences.

2014-10-20 | E-GEOD-54842 | biostudies-arrayexpress