dLKR/SDH regulates hormone-mediated histone arginine methylation and transcription of cell death genes

Dimitrios Cakouros, Kathryn Mills, Donna Denton, Alicia Paterson, Tasman Daish, Sharad Kumar

Research output: Contribution to journalArticlepeer-review

22 Citations (Scopus)

Abstract

The sequential modifications of histones form the basis of the histone code that translates into either gene activation or repression. Nuclear receptors recruit a cohort of histone-modifying enzymes in response to ligand binding and regulate proliferation, differentiation, and cell death. In Drosophila melanogaster,the steroid hormone ecdysone binds its heterodimeric receptor ecdysone receptor/ultraspiracle to spatiotemporally regulate the transcription of several genes. In this study, we identify a novel cofactor, Drosophila lysine ketoglutarate reductase (dLKR)/saccharopine dehydrogenase (SDH), that is involved in ecdysone-mediated transcription. dLKR/SDH binds histones H3 and H4 and suppresses ecdysone-mediated transcription of cell death genes by inhibiting histone H3R17me2 mediated by the Drosophila arginine methyl transferase CARMER. Our data suggest that the dynamic recruitment of dLKR/SDH to ecdysone-regulated gene promoters controls the timing of hormone-induced gene expression. In the absence of dLKR/SDH, histone methylation occurs prematurely, resulting in enhanced gene activation. Consistent with these observations, the loss of dLKR/SDH in Drosophila enhances hormone-regulated gene expression, affecting the developmental timing of gene activation.

Original languageEnglish
Pages (from-to)481-495
Number of pages15
JournalJournal of Cell Biology
Volume182
Issue number3
DOIs
Publication statusPublished or Issued - 11 Aug 2008

ASJC Scopus subject areas

  • Cell Biology

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