Dataset Information

The Memory of Environmental Chemical Exposure in C. elegans Is Dependent on the Jumonji Demethylases jmjd-2 and jmjd-3/utx-1.

ABSTRACT: 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.

SUBMITTER: Camacho J

PROVIDER: S-EPMC6003705 | biostudies-literature | 2018 May

REPOSITORIES: biostudies-literature

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The Memory of Environmental Chemical Exposure in C. elegans Is Dependent on the Jumonji Demethylases jmjd-2 and jmjd-3/utx-1.

Camacho Jessica J Truong Lisa L Kurt Zeyneb Z Chen Yen-Wei YW Morselli Marco M Gutierrez Gerardo G Pellegrini Matteo M Yang Xia X Allard Patrick P

Cell reports 20180501 8

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), hi ...[more]

PMID: 29791850

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Project description:Hypertrophic/dilated cardiomyopathy, often a prequel to heart failure, is accompanied by maladaptive transcriptional changes that contribute to arrythmias and contractile misfunction. Transgenic mice constitutively expressing high levels of calcineurin are known to develop extreme heart hypertrophy, which progresses to dilated cardiomyopathy, and to die several weeks after birth. Here, we characterized aberrant transcriptional and epigenetic pathways in this mouse model and established a pharmacological approach to treat established cardiomyopathy. We found that H3K4me3 (trimethyl histone 3 lysine 4) and H3K9me3 (trimethyl histone 3 lysine 9) Jumonji histone demethylases are markedly increased at the protein level and show enhanced enzymatic activity in diseased hearts. These epigenetic regulators continued to increase with time, further affecting cardiac gene expression. Our findings parallel the lower H3K4me3 and H3K9me3 levels seen in human patients. Inhibition of Jumonji demethylase activities in vivo results in lower histone demethylase enzymatic function in the heart and higher histone methylation levels and leads to partial reduction of heart size, reversal of maladaptive transcriptional programs, improved heart function, and prolonged survival. At the molecular level, target genes of transcription factor myocyte enhancer factor 2 are specifically regulated in response to pharmacological or genetic inhibition of Jumonji demethylases. Similar transcriptional reversal of disease-associated genes is seen in a second disease model based on cardiac mechanical overload. Our findings validate pharmacological inhibitors of Jumonji demethylases as potential therapeutics for the treatment of cardiomyopathies across disease models and provide evidence of the reversal of maladaptive transcriptional reprogramming leading to partial restoration of cardiac function. In addition, this study defines pathways of therapeutic resistance upregulated with disease progression.

Dataset Information

The Memory of Environmental Chemical Exposure in C. elegans Is Dependent on the Jumonji Demethylases jmjd-2 and jmjd-3/utx-1.

Publications

The Memory of Environmental Chemical Exposure in C. elegans Is Dependent on the Jumonji Demethylases jmjd-2 and jmjd-3/utx-1.

Similar Datasets

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