Abstract
BackgroundEpigenetic modifications, particularly DNA methylation and posttranslational histone modifications regulate heritable changes in transcription without changes in the DNA sequence. Despite a number of studies showing clear links between environmental factors and DNA methylation, little is known about the effect of environmental factors on the recently identified histone lysine methylation. Since their identification numerous studies have establish critical role played by these enzymes in mammalian development. ObjectivesIdentification of the Jumonji (Jmj) domain containing histone lysine demethylase have added a new dimension to epigenetic control of gene expression by dynamic regulation of histone methylation marks. The objective of our study was to evaluate the effect of prohexadione and trinexapac, widely used plant growth regulators of the acylcyclohexanediones class, on the enzymatic activity of histone lysine demethylases and histone modifications during the neural stem/progenitor cell differentiation. MethodsHere we show that prohexadione, but not trinexapac, directly inhibits non-heme iron (II), 2-oxoglutarate-dependent histone lysine demethylase such as Jmjd2a. We used molecular modeling to show binding of prohexadione to Jmjd2a. We also performed in vitro demethylation assays to show the inhibitory effect of prohexadione on Jmjd2a. Further we tested this molecule in cell culture model of mouse hippocampal neural stem/progenitor cells to demonstrate its effect toward neuronal proliferation and differentiation. ResultsMolecular modeling studies suggest that prohexadione binds to the 2-oxoglutarate binding site of Jmjd2a demethylase. Treatment of primary neural stem/progenitor cells with prohexadione showed a concentration dependent reduction in their proliferation. Further, the prohexadione treated neurospheres were induced toward neurogenic lineage upon differentiation. ConclusionsOur results describe an important chemico-biological interaction of prohexadione, in light of critical roles played by histone lysine demethylases in human health and diseases.
Highlights
Epigenetics dictates the foundation of cellular growth, differentiation, and identity
Due to structural similarities between 2OG, prohexadione, and trinexapac it has been proposed that prohexadione and trinexapac act as competitive inhibitors of 2OG-dependent enzymes in the gibberellin biosynthetic pathway
Enzymatic assay, and crystal structure of the jumonji domain-2 (Jmjd2) family KDMs are documented in the literature [11,16,17], we focused on Jmjd2a isoform as a representative KDM for docking and in vitro enzymatic studies
Summary
Epigenetics dictates the foundation of cellular growth, differentiation, and identity. Despite a number of studies showing clear links between environmental factors and DNA methylation, little is known about the effect of environmental factors on histone lysine methylation. Despite a number of studies showing clear links between environmental factors and DNA methylation, little is known about the effect of environmental factors on the recently identified histone lysine methylation. Since their identification numerous studies have establish critical role played by these enzymes in mammalian development. Objectives: Identification of the Jumonji (Jmj) domain containing histone lysine demethylase have added a new dimension to epigenetic control of gene expression by dynamic regulation of histone methylation marks.
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