The memory of environmental chemical exposure in C. elegans is dependent on the Jumonji demethylases jmjd-2 and jmjd-3/utx-1
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA450395 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR7010080.fastq.gz | Fastqsanger.gz | |||
| SRR7010074.fastq.gz | Fastqsanger.gz | |||
| SRR7010075.fastq.gz | Fastqsanger.gz | |||
| SRR7010076.fastq.gz | Fastqsanger.gz | |||
| SRR7010077.fastq.gz | Fastqsanger.gz |
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Project description:How artificial environmental cues are biologically integrated and transgenerationally inherited is still poorly understood. Here, we investigate the mechanisms of inheritance of reproductive outcomes elicited by the model environmental chemical Bisphenol A (BPA) in C. elegans. We show that BPA exposure causes the derepression of an epigenetically silenced transgene in the germline for 5 generations, regardless of ancestral response. ChIP-seq, histone modifications quantitation, and immunofluorescence assays revealed that this effect is associated with a reduction of the repressive marks H3K9me3 and H3K27me3 in whole worms and in germline nuclei in the F3 as well as with reproductive dysfunctions including germline apoptosis and embryonic lethality. Furthermore, targeting of the Jumonji demethylases JMJD-2 and JMJD-3/UTX-1 restores H3K9me3 and H3K27me3 levels, respectively, and fully alleviates the BPA-induced transgenerational effects. Together, our results demonstrate the central role of repressive histone modifications in the inheritance of reproductive defects elicited by a common environmental chemical exposure.
2018-04-16 | GSE113187 | GEO
Project description:How artificial environmental cues are biologically integrated and transgenerationally inherited is still poorly understood. Here, we investigate the mechanisms of inheritance of reproductive outcomes elicited by the model environmental chemical Bisphenol A (BPA) in C. elegans. We show that BPA exposure causes the derepression of an epigenetically silenced transgene in the germline for 5 generations, regardless of ancestral response. ChIP-seq, histone modifications quantitation, and immunofluorescence assays revealed that this effect is associated with a reduction of the repressive marks H3K9me3 and H3K27me3 in whole worms and in germline nuclei in the F3 as well as with reproductive dysfunctions including germline apoptosis and embryonic lethality. Furthermore, targeting of the Jumonji demethylases JMJD-2 and JMJD-3/UTX-1 restores H3K9me3 and H3K27me3 levels, respectively, and fully alleviates the BPA-induced transgenerational effects. Together, our results demonstrate the central role of repressive histone modifications in the inheritance of reproductive defects elicited by a common environmental chemical exposure.
2018-04-17 | GSE113266 | GEO
Project description:The memory of environmental chemical exposure in C. elegans is dependent on the Jumonji demethylases jmjd-2 and jmjd-3/utx-1
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Project description:How artificial environmental cues are biologically integrated and transgenerationally inherited is still poorly understood. Here, we investigate the mechanisms of inheritance of reproductive outcomes elicited by the model environmental chemical Bisphenol A in C. elegans. We show that Bisphenol A (BPA) exposure causes the derepression of an epigenomically silenced transgene in the germline for 5 generations, regardless of ancestral response. Chromatin immunoprecipitation sequencing (ChIP-seq), histone modification quantitation, and immunofluorescence assays revealed that this effect is associated with a reduction of the repressive marks H3K9me3 and H3K27me3 in whole worms and in germline nuclei in the F3, as well as with reproductive dysfunctions, including germline apoptosis and embryonic lethality. Furthermore, targeting of the Jumonji demethylases JMJD-2 and JMJD-3/UTX-1 restores H3K9me3 and H3K27me3 levels, respectively, and it fully alleviates the BPA-induced transgenerational effects. Together, our results demonstrate the central role of repressive histone modifications in the inheritance of reproductive defects elicited by a common environmental chemical exposure.
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Project description:Cardiac hypertrophy is a potentially fatal disease characterized by increased cardiomyocyte size, and maladaptive transcriptional remodeling that leads to arrythmias and contractile failure. Transgenic mice constitutively expressing high levels of calcineurin develop extreme heart hypertrophy and generally die within a few weeks of birth. Here, we characterize the transcriptional and epigenetic pathways that are aberrant in this mouse model and establish a pharmacological approach to treating cardiac hypertrophy based on our observation that a subset of histone demethylases of the Jumonji KDM family that act on H3K4me3 or H3K9me3 are markedly increased at the protein level and show enhanced enzymatic activity in diseased hearts. Inhibition of Jumonji demethylases in vivo results in lower histone demethylase enzymatic activity in the heart without toxicity, and leads to partial reduction of heart size, to the reversal of maladaptive transcriptional programs, to improved heart function, and to prolongation of survival. Mechanistically, MEF2, KDM4A and KDM3A target genes are specifically regulated in response to pharmacological or genetic inhibition of Jumonji demethylases and NFAT remains largely cytoplasmic. Similar transcriptional reversal of disease genes is seen in a second disease model based on cardiac mechanical overload, suggesting the generality of this approach. Our findings establish the use of pharmacological inhibitors of Jumonji enzymes as potential therapeutics for the treatment of cardiac hypertrophy across disease models and provides evidence of the reversal of maladaptive transcriptional reprogramming in the heart leading to partial restoration of cardiac function.
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Project description:Cardiac hypertrophy is a potentially fatal disease characterized by increased cardiomyocyte size, and maladaptive transcriptional remodeling that leads to arrythmias and contractile failure. Transgenic mice constitutively expressing high levels of calcineurin develop extreme heart hypertrophy and generally die within a few weeks of birth. Here, we characterize the transcriptional and epigenetic pathways that are aberrant in this mouse model and establish a pharmacological approach to treating cardiac hypertrophy based on our observation that a subset of histone demethylases of the Jumonji KDM family that act on H3K4me3 or H3K9me3 are markedly increased at the protein level and show enhanced enzymatic activity in diseased hearts. Inhibition of Jumonji demethylases in vivo results in lower histone demethylase enzymatic activity in the heart without toxicity, and leads to partial reduction of heart size, to the reversal of maladaptive transcriptional programs, to improved heart function, and to prolongation of survival. Mechanistically, MEF2, KDM4A and KDM3A target genes are specifically regulated in response to pharmacological or genetic inhibition of Jumonji demethylases and NFAT remains largely cytoplasmic. Similar transcriptional reversal of disease genes is seen in a second disease model based on cardiac mechanical overload, suggesting the generality of this approach. Our findings establish the use of pharmacological inhibitors of Jumonji enzymes as potential therapeutics for the treatment of cardiac hypertrophy across disease models and provides evidence of the reversal of maladaptive transcriptional reprogramming in the heart leading to partial restoration of cardiac function.
2022-02-08 | GSE168847 | GEO
Project description:To understand the role of the H3K27me3 demethylases, UTX and JMJD3, in B cell differentiation. Naïve B cells were cultures ex vivo with LPS, IL-2,IL-5 in the presence of DMSO or GSK-J4, UTX/JMJD3 inhibitor. Plasmablasts and activated B cells were magnetically enriched after 3 days of culture.
2021-11-16 | GSE158139 | GEO
Project description:Cardiac hypertrophy is a potentially fatal disease characterized by increased cardiomyocyte size, and maladaptive transcriptional remodeling that leads to arrythmias and contractile failure. Transgenic mice constitutively expressing high levels of calcineurin develop extreme heart hypertrophy and generally die within a few weeks of birth. Here, we characterize the transcriptional and epigenetic pathways that are aberrant in this mouse model and establish a pharmacological approach to treating cardiac hypertrophy based on our observation that a subset of histone demethylases of the Jumonji KDM family that act on H3K4me3 or H3K9me3 are markedly increased at the protein level and show enhanced enzymatic activity in diseased hearts. Inhibition of Jumonji demethylases in vivo results in lower histone demethylase enzymatic activity in the heart without toxicity, and leads to partial reduction of heart size, to the reversal of maladaptive transcriptional programs, to improved heart function, and to prolongation of survival. Mechanistically, MEF2, KDM4A and KDM3A target genes are specifically regulated in response to pharmacological or genetic inhibition of Jumonji demethylases and NFAT remains largely cytoplasmic. Similar transcriptional reversal of disease genes is seen in a second disease model based on cardiac mechanical overload, suggesting the generality of this approach. Our findings establish the use of pharmacological inhibitors of Jumonji enzymes as potential therapeutics for the treatment of cardiac hypertrophy across disease models and provides evidence of the reversal of maladaptive transcriptional reprogramming in the heart leading to partial restoration of cardiac function.
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Project description:T-cell acute lymphoblastic leukemia (T-ALL) is an immature hematopoietic malignancy driven mainly by oncogenic activation of NOTCH1 signaling. In this study we abrogated the expression of JMJD3 (KDM6B) and UTX (KDM6A) H3K27me3 demethylases in human T-ALL lines and assayed for genome-wide changes in H3K27me3 levels. This piece of data was further integrated to expression changes using RNA sequencing in the same cells as well as ChIP-Sequencing analysis of H3K27me3 and JMJD3 genome-wide analysis from treatment of T-ALL lines with the GSKJ4 inhibitor. These results, coupled to genomic analysis of primary samples for the genomic status of the UTX gene in T-ALL, helped us to identify a hitherto unknown role of JMJD3 as an oncogenice facilitator in leukemia whereas UTX seems to play a tumor suppressor role. Half to one million cells were treated with micrococcal nuclease (MNASE) to generate mononucleosomal particles and an adaptation of the Upstate ChIP protocol was used.
2014-10-01 | E-GEOD-56692 | biostudies-arrayexpress
Project description:T-cell acute lymphoblastic leukemia (T-ALL) is an immature hematopoietic malignancy driven mainly by oncogenic activation of NOTCH1 signaling. In this study we abrogated the expression of JMJD3 (KDM6B) and UTX (KDM6A) H3K27me3 demethylases in human T-ALL lines and assayed for genome-wide expression changes using RNA sequencing. This piece of data was further integrated to ChIP-Sequencing analysis of H3K27me3 from the same treatment as well as H3K27me3 and JMJD3 genome-wide analysis from treatment of T-ALL lines with the GSKJ4 inhibitor. These results, coupled to genomic analysis of primary samples for the genomic status of the UTX gene in T-ALL, helped us to identify a hitherto unknown role of JMJD3as an oncogenice facilitator in leukemia whereas UTX seems to play a tumor suppressor role. Whole RNA was extracted from 1-5 million T-ALL (lines) cells or primary cells using the RNAeasy kit (Qiagen) according to the manufacturer’s protocol. Poly-A+ (magnetic oligodT-containing beads (Invitrogen)) or Ribominus RNA was used for library preparation. cDNA preparation and strand-specific library construction was performed using the dUTP method. Libraries were sequenced on the Illumina HiSeq 2000 using 50bp single-read method. Differential gene expression analysis was performed for each matched knockdown vs control pairs, separately in each biological or technical replicate in each of two cell lines (CUTLL1, CEM). Three types of comparisons were tested: (a) JMJD3 knockdown vs Renilla, (b) JMJD3 knockdown vs UTX knockdown, and (c) UTX knockdown vs Renilla. Analysis was performed using both DEGseq and Cufflinks packages leading to very similar conclusions.
2014-10-01 | E-GEOD-56689 | biostudies-arrayexpress