Cellular differentiation is dependent on global shifts in genomic expression patterns and preservation of inherited transcriptional states throughout development. This transcriptional memory can be translated directly through promoter DNA methylation or more indirectly through chromatin structure. These epigenetic changes are dynamic, extensively utilized mechanisms of gene and genome regulation. Mammalian gametogenesis requires numerous such epigenetic changes to accompany the transition from somatic, diploid precursors to mature, haploid gametes. This transition is important for the progression through meiosis, which itself requires the action of macromolecular complexes to manage the series of events entailing meiotic recombination between homologous chromosomes. Embryonic epigenetic states are first erased and reprogrammed during the development of primordial germ cells. Later, as germ cells differentiate, faithful execution of the meiotic program requires that their genomes undergo large-scale changes to histone and DNA modifications as well as to chromatin structure, all of which requiring the action of a large number of chromatin modifying pathways. The experiments outlined in this proposal are focused on elucidating the role of chromatin modifiers as facilitators of homeostasis and differentiation during mammalian spermatogenesis.

Public Health Relevance

Many human diseases are the result of incorrect interpretation of genome sequence due to abnormalities in the structure of chromatin that packages DNA in the nucleus (epigenetics). Studies on chromatin modifying proteins have demonstrated their ability to disrupt histone-DNA contacts and reposition nucleosomes, thereby regulating global gene expression. Genetic experiments that elucidate the biological specificity of these proteins, along with the abnormal outcomes associated with disease states when inappropriately expressed, ultimately may lead to targeted disease treatments.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM101974-29
Application #
9257435
Study Section
Development - 2 Study Section (DEV2)
Program Officer
Carter, Anthony D
Project Start
1989-12-01
Project End
2020-03-31
Budget Start
2017-04-01
Budget End
2018-03-31
Support Year
29
Fiscal Year
2017
Total Cost
Indirect Cost
Name
University of North Carolina Chapel Hill
Department
Genetics
Type
Schools of Medicine
DUNS #
608195277
City
Chapel Hill
State
NC
Country
United States
Zip Code
27599
Smith, Keriayn N; Starmer, Joshua; Magnuson, Terry (2018) Interactome determination of a Long Noncoding RNA implicated in Embryonic Stem Cell Self-Renewal. Sci Rep 8:17568
Wijayatunge, Ranjula; Liu, Fang; Shpargel, Karl B et al. (2018) The histone demethylase Kdm6b regulates a mature gene expression program in differentiating cerebellar granule neurons. Mol Cell Neurosci 87:4-17
Smith, Keriayn N; Starmer, Joshua; Miller, Sarah C et al. (2017) Long Noncoding RNA Moderates MicroRNA Activity to Maintain Self-Renewal in Embryonic Stem Cells. Stem Cell Reports 9:108-121
Mu, Weipeng; Starmer, Joshua; Shibata, Yoichiro et al. (2017) EZH1 in germ cells safeguards the function of PRC2 during spermatogenesis. Dev Biol 424:198-207
Shpargel, Karl B; Starmer, Joshua; Wang, Chaochen et al. (2017) UTX-guided neural crest function underlies craniofacial features of Kabuki syndrome. Proc Natl Acad Sci U S A 114:E9046-E9055
Serber, Daniel W; Runge, John S; Menon, Debashish U et al. (2016) The Mouse INO80 Chromatin-Remodeling Complex Is an Essential Meiotic Factor for Spermatogenesis. Biol Reprod 94:8
Starmer, Joshua; Magnuson, Terry (2016) Detecting broad domains and narrow peaks in ChIP-seq data with hiddenDomains. BMC Bioinformatics 17:144
Yang, Yang; Poe, Jonathan C; Yang, Lisong et al. (2016) Rad18 confers hematopoietic progenitor cell DNA damage tolerance independently of the Fanconi Anemia pathway in vivo. Nucleic Acids Res 44:4174-88
Cook, Kevin D; Shpargel, Karl B; Starmer, Joshua et al. (2015) T Follicular Helper Cell-Dependent Clearance of a Persistent Virus Infection Requires T Cell Expression of the Histone Demethylase UTX. Immunity 43:703-14
Calabrese, J Mauro; Starmer, Joshua; Schertzer, Megan D et al. (2015) A survey of imprinted gene expression in mouse trophoblast stem cells. G3 (Bethesda) 5:751-9

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