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Genome-wide Kdm4 histone demethylase transcriptional regulation in Drosophila

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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.

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Acknowledgements

This work was supported by an NIH Grant (R01CA131326) to WXL. AT was supported by the Shriners Hospitals Research Fellowship #84293. We would like to acknowledge Laura Goodfield, Yashoda Dhole, Paris Karniadakis, Jacqueline Baba and Ved Dhole for their input.

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Authors and Affiliations

  1. Department of Surgery, Massachusetts General Hospital and Harvard Medical School, 50 Blossom St., Their 340, Boston, MA, 02114, USA

    Amy Tsurumi

  2. Department of Microbiology and Immunology, Harvard Medical School, 77 Ave. Louis Pasteur, Boston, MA, 02115, USA

    Amy Tsurumi

  3. Shriners Hospitals for Children-Boston®, 51 Blossom St., Boston, MA, 02114, USA

    Amy Tsurumi

  4. Department of Medicine, University of California at San Diego, 9500 Gilman Dr., La Jolla, CA, 92093, USA

    Shuang Xue, Lin Zhang, Jinghong Li & Willis X. Li

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  1. Amy Tsurumi
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Tsurumi, A., Xue, S., Zhang, L. et al. Genome-wide Kdm4 histone demethylase transcriptional regulation in Drosophila. Mol Genet Genomics 294, 1107–1121 (2019). https://doi.org/10.1007/s00438-019-01561-z

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