Dataset Information

Genome-wide Kdm4 histone demethylase transcriptional regulation in Drosophila.

ABSTRACT: The histone lysine demethylase 4 (Kdm4/Jmjd2/Jhdm3) family is highly conserved across species and reverses di- and tri-methylation of histone H3 lysine 9 (H3K9) and lysine 36 (H3K36) at the N-terminal tail of the core histone H3 in various metazoan species including Drosophila, C.elegans, zebrafish, mice and humans. Previous studies have shown that the Kdm4 family plays a wide variety of important biological roles in different species, including development, oncogenesis and longevity by regulating transcription, DNA damage response and apoptosis. Only two functional Kdm4 family members have been identified in Drosophila, compared to five in mammals, thus providing a simple model system. Drosophila Kdm4 loss-of-function mutants do not survive past the early 2nd instar larvae stage and display a molting defect phenotype associated with deregulated ecdysone hormone receptor signaling. To further characterize and identify additional targets of Kdm4, we employed a genome-wide approach to investigate transcriptome alterations in Kdm4 mutants versus wild-type during early development. We found evidence of increased deregulated transcripts, presumably associated with a progressive accumulation of H3K9 and H3K36 methylation through development. Gene ontology analyses found significant enrichment of terms related to the ecdysteroid hormone signaling pathway important in development, as expected, and additionally previously unidentified potential targets that warrant further investigation. Since Kdm4 is highly conserved across species, our results may be applicable more widely to other organisms and our genome-wide dataset may serve as a useful resource for further studies.

SUBMITTER: Tsurumi A

PROVIDER: S-EPMC6813854 | biostudies-literature | 2019 Oct

REPOSITORIES: biostudies-literature

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Genome-wide Kdm4 histone demethylase transcriptional regulation in Drosophila.

Tsurumi Amy A Xue Shuang S Zhang Lin L Li Jinghong J Li Willis X WX

Molecular genetics and genomics : MGG 20190424 5

The histone lysine demethylase 4 (Kdm4/Jmjd2/Jhdm3) family is highly conserved across species and reverses di- and tri-methylation of histone H3 lysine 9 (H3K9) and lysine 36 (H3K36) at the N-terminal tail of the core histone H3 in various metazoan species including Drosophila, C.elegans, zebrafish, mice and humans. Previous studies have shown that the Kdm4 family plays a wide variety of important biological roles in different species, including development, oncogenesis and longevity by regulati ...[more]

PMID: 31020413

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Project description:BackgroundParkinson's disease (PD) is a complex, age-related neurodegenerative disorder of largely unknown etiology. PD is strongly associated with mitochondrial respiratory dysfunction, which can lead to epigenetic dysregulation and specifically altered histone acetylation. Nevertheless, and despite the emerging role of epigenetics in age-related brain disorders, the question of whether aberrant histone acetylation is involved in PD remains unresolved.MethodsWe studied fresh-frozen brain tissue from two independent cohorts of individuals with idiopathic PD (n = 28) and neurologically healthy controls (n = 21). We performed comprehensive immunoblotting to identify histone sites with altered acetylation levels in PD, followed by chromatin immunoprecipitation sequencing (ChIP-seq). RNA sequencing data from the same individuals was used to assess the impact of altered histone acetylation on gene expression.ResultsImmunoblotting analyses revealed increased acetylation at several histone sites in PD, with the most prominent change observed for H3K27, a marker of active promoters and enhancers. ChIP-seq analysis further indicated that H3K27 hyperacetylation in the PD brain is a genome-wide phenomenon with a strong predilection for genes implicated in the disease, including SNCA, PARK7, PRKN and MAPT. Integration of the ChIP-seq with transcriptomic data from the same individuals revealed that the correlation between promoter H3K27 acetylation and gene expression is attenuated in PD patients, suggesting that H3K27 acetylation may be decoupled from transcription in the PD brain. Strikingly, this decoupling was most pronounced among nuclear-encoded mitochondrial genes, corroborating the notion that impaired crosstalk between the nucleus and mitochondria is involved in the pathogenesis of PD. Our findings independently replicated in the two cohorts.ConclusionsOur findings strongly suggest that aberrant histone acetylation and altered transcriptional regulation are involved in the pathophysiology of PD. We demonstrate that PD-associated genes are particularly prone to epigenetic dysregulation and identify novel epigenetic signatures associated with the disease.

Project description:BackgroundHistone chaperones modulate chromatin architecture and hence play a pivotal role in epigenetic regulation of gene expression. In contrast to their animal and yeast counterparts, not much is known about plant histone chaperones. To gain insights into their functions in plants, we sought to identify histone chaperones from two model plant species and investigated their phylogeny, domain architecture and transcriptional profiles to establish correlation between their expression patterns and potential role in stress physiology and plant development.ResultsThrough comprehensive whole genome analyses of Arabidopsis and rice, we identified twenty-two and twenty-five genes encoding histone chaperones in these plants, respectively. These could be classified into seven different families, namely NAP, CAF1, SPT6, ASF1, HIRA, NASP, and FACT. Phylogenetic analyses of histone chaperones from diverse organisms including representative species from each of the major plant groups, yeast and human indicated functional divergence in NAP and CAF1C in plants. For the largest histone chaperone family, NAP, phylogenetic reconstruction suggested the presence of two distinct groups in plants, possibly with differing histone preferences. Further, to comment upon their physiological roles in plants, we analyzed their expression at different developmental stages, across various plant tissues, and under biotic and abiotic stress conditions using pre-existing microarray and qRT-PCR. We found tight transcriptional regulation of some histone chaperone genes during development in both Arabidopsis and rice, suggesting that they may play a role in genetic reprogramming associated with the developmental process. Besides, we found significant differential expression of a few histone chaperones under various biotic and abiotic stresses pointing towards their potential function in stress response.ConclusionsTaken together, our findings shed light onto the possible evolutionary trajectory of plant histone chaperones and present novel prospects about their physiological roles. Considering that the developmental process and stress response require altered expression of a large array of genes, our results suggest that some plant histone chaperones may serve a regulatory role by controlling the expression of genes associated with these vital processes, possibly via modulating chromatin dynamics at the corresponding genetic loci.

Dataset Information

Genome-wide Kdm4 histone demethylase transcriptional regulation in Drosophila.

Publications

Genome-wide Kdm4 histone demethylase transcriptional regulation in Drosophila.

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