The long term objective of my laboratory is to gain a molecular understanding of epigenetic processes that regulate chromatin structure and gene expression. Towards this end we have identified a novel tandem kinase in Drosophila, JIL-1, that localizes specifically to the gene-active interband regions of the larval polytene chromosomes, phosphorylates histone H3S10, and is enriched almost two-fold on the transcriptionally hyperactive male larval polytene X chromosome. In JIL-1 hypomorphs orderly interband regions of polytene chromosomes are disrupted and the chromosome arms highly condensed. Position effect variegation (PEV) in Drosophila has served as a major paradigm for the identification and genetic analysis of evolutionarily conserved determinants of epigenetic regulation of chromatin structure and gene silencing and we provide evidence that loss-of-function alleles of the JIL-1 histone H3S10 kinase can act either as suppressors or enhancers of PEV depending on the chromatin environment of the reporter locus. These effects on PEV were correlated with the spreading of the major heterochromatin markers dmH3K9 and HP1 to ectopic locations on the chromosome arms with the most pronounced upregulation found on the male and female X chromosomes. Based on these findings we propose a model where JIL-1 kinase activity and phosphorylation of histone H3S10 at interphase functions to antagonize heterochromatization by regulating a dynamic balance between factors promoting repression and activation of gene expression.
Gene silencing is a critical developmental process relevant to many human health problems that include cancer. Furthermore, JIL-1 is the Drosophila homolog of the mammalian MSK1 kinase which also functions as a regulator of chromatin structure by phosphorylating the histone H3S10 residue. At present the mammalian studies have been directed towards analyzing histone phosphorylation in the context of immediate early gene transcription. However, our results suggest that the concept of histone phosphorylation should be expanded to be considered in the context of the regulation of gene silencing as well. Thus, our studies will serve to provide general insights into the molecular mechanisms of how kinase activity modulates chromatin structure and gene regulation that are directly relevant to humans.
Funding Organization: National Institutes of Health