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.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
2R01GM055360-14A1
Application #
8238813
Study Section
Molecular Genetics B Study Section (MGB)
Program Officer
Carter, Anthony D
Project Start
1998-05-01
Project End
2016-03-31
Budget Start
2012-06-25
Budget End
2013-03-31
Support Year
14
Fiscal Year
2012
Total Cost
$345,979
Indirect Cost
$124,979
Name
University of Pennsylvania
Department
Anatomy/Cell Biology
Type
Schools of Medicine
DUNS #
042250712
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
Luense, Lacey J; Wang, Xiaoshi; Schon, Samantha B et al. (2016) Comprehensive analysis of histone post-translational modifications in mouse and human male germ cells. Epigenetics Chromatin 9:24
Bryant, Jessica M; Donahue, Greg; Wang, Xiaoshi et al. (2015) Characterization of BRD4 during mammalian postmeiotic sperm development. Mol Cell Biol 35:1433-48
Hu, Jialei; Donahue, Greg; Dorsey, Jean et al. (2015) H4K44 Acetylation Facilitates Chromatin Accessibility during Meiosis. Cell Rep 13:1772-80
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 :
Bryant, Jessica M; Govin, Jérôme; Zhang, Liye et al. (2012) The linker histone plays a dual role during gametogenesis in Saccharomyces cerevisiae. Mol Cell Biol 32:2771-83
Mallory, Michael J; Law, Michael J; Sterner, David E et al. (2012) Gcn5p-dependent acetylation induces degradation of the meiotic transcriptional repressor Ume6p. Mol Biol Cell 23:1609-17
Bryant, Jessica M; Berger, Shelley L (2012) Low-hanging fruit: targeting Brdt in the testes. EMBO J 31:3788-9
Shieh, Grace S; Pan, Chin-Hua; Wu, Jia-Hong et al. (2011) H2B ubiquitylation is part of chromatin architecture that marks exon-intron structure in budding yeast. BMC Genomics 12:627
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

Showing the most recent 10 out of 18 publications