Abstract
Jumonji (JmjC) domain proteins influence gene expression and chromatin organization by way of histone demethylation, which provides a means to regulate the activity of genes across the genome. JmjC proteins have been associated with many human diseases including various cancers, developmental and neurological disorders, however, the shared biology and possible common contribution to organismal development and tissue homeostasis of all JmjC proteins remains unclear. Here, we systematically tested the function of all 13 Drosophila JmjC genes. Generation of molecularly defined null mutants revealed that loss of 8 out of 13 JmjC genes modify position effect variegation (PEV) phenotypes, consistent with their ascribed role in regulating chromatin organization. However, most JmjC genes do not critically regulate development, as 10 members are viable and fertile with no obvious developmental defects. Rather, we find that different JmjC mutants specifically alter the phenotypic outcomes in various sensitized genetic backgrounds. Our data demonstrate that, rather than controlling essential gene expression programs, Drosophila JmjC proteins generally act to “fine-tune” different biological processes.
Highlights
The methylation of specific lysine residues on histone proteins has a direct impact on chromatin organization and gene expression programs[1, 2]
Mutations in KDM4A and KDM4B interfere with transcriptional activation of the ecdysone receptor[20] and KDM4B heterozygotes are more sensitive to p53-dependent response to UV radiation[21]
The KDM3KO allele, a portion of the open reading frame (ORF) remained in an exogenous location within the targeting vector
Summary
The methylation of specific lysine residues on histone proteins has a direct impact on chromatin organization and gene expression programs[1, 2]. These genes can be placed into seven JmjC subgroups based on shared protein domains with their human homologs[4] (Fig. 1) This reduced redundancy greatly facilitates the functional characterization of this gene family. Mutations in KDM4A and KDM4B interfere with transcriptional activation of the ecdysone receptor[20] and KDM4B heterozygotes are more sensitive to p53-dependent response to UV radiation[21] While these examples focused on specific effects on single genes or pathways, a null mutant of KDM4A has been shown to. Several JmjC mutants affect different genetic backgrounds sensitized for various molecular pathways These results indicate that modulation of JmjC gene function can influence gene expression programs in a variety of contexts
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