Dynamic changes in histone modification underlie the transition of gametic chromatin to embryonic chromatin. These changes are thought to be required for initiation of embryonic gene transcription and acquisition of pluripotency. Abnormalities in these transitions are likely to result in embryonic arrest at early preimplantation stages. Early embryonic mortality is a major cause of infertility in dairy cattle and humans. In bovine embryos, methylation of histone H3 lysine 27 is one of the epigenetic marks that are dynamically remodeled. Trimethylation of histone H3 lysine 27 is associated with silencing of transcription. We hypothesize that JMJD3, a histone H3 lysine 27 demethylases, is required for removal of methylation marks from H3K27, which in turn allows the initiation of embryonic gene transcription and normal embryo development. To test this hypothesis we will induce downregulation of JMJD3 in bovine oocytes and preimplantation embryos by siRNA injection.
Specific Aim 1 will determine whether maternally inherited JMJD3 is required for normal bovine embryonic development.
Specific Aim 2 will make use of chromatin immunoprecipitation to assess the role of JMJD3 on histone methylation reprogramming at the time of embryonic genome activation.
Specific aim 3 is designed to examine the role of JMJD3 on genome activation by analyzing the transcriptome of early embryos using RNA-seq. Together; these experiments will expand our understanding of the basic mechanisms underlying embryonic development. This information will aid in developing diagnostic tools and interventions to treat infertility disorders in animals and people. Also, uncovering the nuclear reprogramming mechanisms elicited by the oocyte will help improve the success of somatic cell nuclear transfer for the generation of cloned animals for agricultural and biomedical applications and autologous stem cells for regenerative medicine applications.

Public Health Relevance

A greater understanding of the biological mechanisms regulating epigenetic transformation during early embryonic development is critical to addressing problems of embryonic lethality observed in the agricultural production and human fertility fields. Results from this study will have direct impacts on the diagnosis and treatment of animal and human fertility disorders, while simultaneously bettering foundational knowledge that can be applied to nuclear reprogramming methodologies necessary for the generation of cloned animals and pluripotent stem cells.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Research Project (R01)
Project #
4R01HD070044-05
Application #
8977418
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Ravindranath, Neelakanta
Project Start
2012-03-01
Project End
2017-12-31
Budget Start
2016-01-01
Budget End
2017-12-31
Support Year
5
Fiscal Year
2016
Total Cost
Indirect Cost
Name
University of California Davis
Department
Veterinary Sciences
Type
Earth Sciences/Resources
DUNS #
047120084
City
Davis
State
CA
Country
United States
Zip Code
95618
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Chung, Nhi; Bogliotti, Yanina S; Ding, Wei et al. (2017) Active H3K27me3 demethylation by KDM6B is required for normal development of bovine preimplantation embryos. Epigenetics 12:1048-1056
Ferré, Luis B; Bogliotti, Yanina; Chitwood, James L et al. (2017) Effect of spermatozoa motility hyperactivation factors and gamete coincubation duration on in vitro bovine embryo development using flow cytometrically sorted spermatozoa. Reprod Fertil Dev 29:805-814
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Reyes, Juan M; Ross, Pablo J (2016) Cytoplasmic polyadenylation in mammalian oocyte maturation. Wiley Interdiscip Rev RNA 7:71-89
Bogliotti, Yanina S; Vilarino, Marcela; Ross, Pablo J (2016) Laser-assisted Cytoplasmic Microinjection in Livestock Zygotes. J Vis Exp :
Soto, Delia A; Ross, Pablo J (2016) Pluripotent stem cells and livestock genetic engineering. Transgenic Res 25:289-306
Canovas, Sebastian; Ross, Pablo Juan (2016) Epigenetics in preimplantation mammalian development. Theriogenology 86:69-79

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