Histone H4 limits transcription of the histone locus in Drosophila
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The expression of core histone genes is coupled to DNA replication of the genome to support chromatin packaging. In Drosophila, core histone genes are repeated in one locus as a 100-copy array and forms the Histone Locus Body; these multiple copies support varying rates of cell proliferation in different developmental stages and various tissues of the animal. We show here that the Drosophila Histone Locus Body contains a mix of active and silenced units. In the male germline reporter histone repeat units are strongly silenced, and we used this setting to test the dependence of expression on chromatin factors and histones. We find that silenced histone genes are induced in response to demand for histones, and from a selected survey we identify that only the H4 histone is required for reporter silencing. Further, histone H4 protein localizes to the Histone Locus Body and is most enriched immediately after S phase of the cell cycle. This argues for a role of histone H4 in coupling the demand for histones for chromatin packaging to histone gene expression. Binding patterns of the NPAT regulatory factor and RNA Polymerase II in K562 cells suggests that this regulatory principle also operates in human cells.
Author Summary
Cell proliferation in eukaryotes requires the coordination of DNA replication to duplicate the genome and synthesis of new histones to package that DNA. Drosophila melanogaster has a single array of histone genes, where some are actively transcribed and others are silenced. Here, we present evidence that the number of activated genes responds to the demand for histones during DNA replication. We identify one histone protein as a factor that localizes to the histone gene array, and that reduced levels of this histone induce the expression of otherwise silenced histone genes. In human cells, the gene encoding this same histone is the predominant target for activating transcription proteins, and is expressed more highly than other histones. The amount of this one histone may serve to sense the demand for histones during DNA replication, so that increased levels of this histone when DNA replication is complete represses histone gene expression.
