Packing for the germy: the role of histone H4 Ser1 phosphorylation in chromatin compaction and germ cell development.

Genetic and epigenetic information is passed to the next generation through germ cells. In this issue of Genes and Development, Krishnamoorthy et al. (2006) have elegantly demonstrated that a conserved histone modification, phosphorylation of Ser1 on histone 4 (H4 S1ph) is involved in chromatin compaction during sporulation in yeast, and that it is an evolutionarily conserved mark found during Drosophila melanogaster and mouse germ cell development. Post-translational modifications of core histones (PTMs) and incorporation of histone variants/replacement proteins during gametogenesis provide an exceptional example of the relationship between chromatin structure and function. In these instances, histones fulfill their more traditional role as structural regulators and DNA packaging proteins, while providing modificationor variant-specific regulation. Significant changes in chromatin architecture are mediated in part by evolutionarily conserved modifications of histone within the nucleosomes, including ubiquitination, methylation, acetylation, and phosphorylation (Workman and Kingston 1998; Shilatifard 2006). These histone modifications serve to alter chromatin structure and thus regulate transcription factor accessibility to chromatin and affect transcriptional readout. During metazoan gametogenesis, cells incorporate somatic and gamete-specific histone variants, as well as generalized histone modifications into their chromatin prior to replacement by DNA packaging proteins (Lewis et al. 2003). Spermatogenesis in Drosophila requires the differentiation of round spermatids into an elongated, needle-like structure, with a 200-fold drop in nuclear volume. This is accomplished in part by modification of histones, as well as a highly orchestrated succession of histone replacements by sperm-specific histone variants, then by basic transition proteins, and finally protamines (Sassone-Corsi 2002; Govin et al. 2004; Kimmins and Sassone-Corsi 2005). The appearance of these new histone subtypes and specific histone modification patterns and their correlation with genome compaction, sperm function, and increased fertility, comprise a germ cellspecific histone modification pattern that alters chromatin structure during meiosis. Saccharomyces cerevisae must protect its genome from damage while simultaneously replicating, recombining, and properly segregating haploid genomes to individual spores. In response to nutrient deprivation, diploid S. cerevisae cells undergo meiosis to produce four stable, metabolically inert haploid spores. Of ∼6000 protein-encoding genes in yeast, >1000 show significant changes in expression during the four stages of sporulation—early, middle, mid-late, and late (Chu et al. 1998). These stages result from a sequential cascade of transcription factors and a specialized mitogen-activated protein (MAP) kinase signaling pathway. During meiosis there is strong correlation between a gene’s expression pattern and its involvement in a particular biological process. Early genes are typically involved in pairing of homologous chromosomes and recombination, middle genes are required for nuclear division and spore formation, and mid-late genes include those necessary for the outer layer of the spore wall (Chu et al. 1998). The metaphase peak of post-translational phosphorylation of S10 of histone H3 from late G2 to telophase is a hallmark of mitosis and meiosis in yeast and metazoan species, and this particular modification correlates with chromatin condensation (Hsu et al. 2000; Nowak and Corces 2004). However, mutations altering S10 of H3 do not alter mitosis, meiosis, or cell growth, suggesting a possible redundancy of its function (Hsu et al. 2000; Barber et al. 2004). In this issue of Genes and Development, Krishnamoorthy et al. (2006) re-examined the function of the previously described phosphorylation of S1 of histone H4 in chromatin compaction during sporulation. They found H4Ser1ph to be required for proper chromatin compaction during sporulation, and also for gametogenesis. It is significant that this histone modification is evolutionarily conserved, from Drosophila to mammals. Corresponding author. E-MAIL shilatia@slu.edu; FAX (314) 977-5737. Article is online at http://www.genesdev. org/cgi/doi/10.1101/gad.1477706.