Dynamic epigenetic alteration is central to differentiation of mammalian sperm, however the nature of these changes remains largely unknown. We are using the process of sporulation in the budding yeast S. cerevisiae, as a tractable model for mammalian spermatogenesis, to uncover dynamic chromatin and epigenetic regulation of transcription, meiosis and chromatin compaction. Our previous observations indicate that there are dramatic temporal changes in chromatin during sporulation, including histone modifications and other alterations. Further, our results indicate that mouse sperm differentiation involves similar temporal sequences of histone modifications, which are analogous in timing to the yeast. This conservation of the pattern of histone modifications during gametogenesis from yeast to mammals, strongly indicates that epigenetic regulation is fundamental to the normal process of chromatin restructuring during gametogenesis. Our hypothesis is that chromatin modulation is a highly evolutionarily conserved process in gametogenesis, and thus is a key regulatory feature of both yeast sporulation and mammalian spermatogenesis. We will address chromatin mechanisms during gametogenesis, through the following specific aims: (1) investigate chromatin mechanisms that operate through histones H3 and H4, including novel post-translational modifications and other regulatory features, identified via mutational screening in the previous funding period, (2) complete screening for histone substitution mutations in histone H2A and H2B that decrease or increase sporulation, and unravel their mechanisms through post-translational modifications, and other regulatory mechanisms, (3) examine linker histone Hho1-mediated mechanisms involved in meiotic gene transcriptional repression and post-meiotic chromatin compaction. As an important part of our proposal, we will determine whether these novel chromatin alterations are conserved during mouse spermatogenesis. Overall, results from these studies will provide novel views of dynamic changes in chromatin structure and function.

Public Health Relevance

We previously discovered novel epigenetic modifications during mouse spermatogenesis, starting from a model system in a simple organism, yeast. In this proposal, we will discover additional epigenetic changes in yeast, and determine whether they are conserved in the mouse process. Results from this study will inform understanding of epigenetic regulation of normal human spermatogenesis and dysfunction in male infertility.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Research Project (R01)
Project #
Application #
Study Section
Molecular Genetics B Study Section (MGB)
Program Officer
Carter, Anthony D
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of Pennsylvania
Anatomy/Cell Biology
Schools of Medicine
United States
Zip Code
Bryant, Jessica M; Meyer-Ficca, Mirella L; Dang, Vanessa M et al. (2013) Separation of spermatogenic cell types using STA-PUT velocity sedimentation. J Vis Exp :
Trujillo, Kelly M; Tyler, Rebecca K; Ye, Chaoyang et al. (2011) A genetic and molecular toolbox for analyzing histone ubiquitylation and sumoylation in yeast. Methods 54:296-303
Edwards, Christopher R; Dang, Weiwei; Berger, Shelley L (2011) Histone H4 lysine 20 of Saccharomyces cerevisiae is monomethylated and functions in subtelomeric silencing. Biochemistry 50:10473-83
Govin, Jerome; Schug, Jonathan; Krishnamoorthy, Thanuja et al. (2010) Genome-wide mapping of histone H4 serine-1 phosphorylation during sporulation in Saccharomyces cerevisiae. Nucleic Acids Res 38:4599-606
Govin, Jerome; Dorsey, Jean; Gaucher, Jonathan et al. (2010) Systematic screen reveals new functional dynamics of histones H3 and H4 during gametogenesis. Genes Dev 24:1772-86
Govin, Jerome; Berger, Shelley L (2009) Genome reprogramming during sporulation. Int J Dev Biol 53:425-32
Zhang, Xiao-Yong; Varthi, Maya; Sykes, Stephen M et al. (2008) The putative cancer stem cell marker USP22 is a subunit of the human SAGA complex required for activated transcription and cell-cycle progression. Mol Cell 29:102-11
Walter, Wendy; Clynes, David; Tang, Yong et al. (2008) 14-3-3 interaction with histone H3 involves a dual modification pattern of phosphoacetylation. Mol Cell Biol 28:2840-9
Ingvarsdottir, Kristin; Edwards, Chris; Lee, Min Gyu et al. (2007) Histone H3 K4 demethylation during activation and attenuation of GAL1 transcription in Saccharomyces cerevisiae. Mol Cell Biol 27:7856-64
Kao, Cheng-Fu; Hillyer, Cory; Tsukuda, Toyoko et al. (2004) Rad6 plays a role in transcriptional activation through ubiquitylation of histone H2B. Genes Dev 18:184-95