Heterochromatin formation is essential for chromosome segregation, epigenetic silencing and X chromosome inactivation. In spite of their biological significance, the mechanisms involved in the establishment of heterochromatin domains during oogenesis are currently unknown. The focus of this proposal will be on two members of the SWIISNF2 family of chromatin remodeling proteins Lsh and A TRX known to have a role in DNA methylation. This proposal is based on the following hypotheses 1) that Lsh is essential for genomic stability during female meiosis;and 2) that both ATRX and Lsh are essential for centromeric heterochromatin formation and epigenetic gene silencing during mouse oocyte growth. The specific objectives include (1) To determine the role of the lymphocyte specific helicase (Lsh) during prophase I of meiosis;(2) To determine whether the Lsh protein has a functional role in centromeric heterochromatin formation during mouse oocyte growth. A transgenic knockout mouse model will be used to determine the mechanisms interfering with homologous chromosome synapsis in Lsh null oocytes during prophase I of meiosis. Particular emphasis will be placed to characterize the molecular interactions between Lsh and ATRX during oogenesis and to determine their functional significance for centromeric heterochromatin formation. These studies will provide critical information regarding the relationship between DNA methylation, heterochromatin formation and epigenetic gene silencing during female meiosis, as well as the mechanisms affecting meiotic centromere function, genomic stability and the molecular mechanisms contributing to the onset of aneuploidy in the mammalian oocyte and pre-implantation embryo.

Public Health Relevance

NIH Grant: 1-RO1-HD-042740-01A2 Title: Epigenetic Control of Heterochromatin Formation in the Mammalian Oocyte Principal Investigator: Rabindranath De La Fuente DVM., Ph.D. Meiosis is a critical cell division, specific to the germ line of all animals. During meiosis, complex mechanisms regulate accurate chromosome segregation in order to produce mature gametes. This project seeks to establish the role of the chromatin remodeling proteins Lsh and ATRX in chromosome segregation in mammalian oocytes.

National Institute of Health (NIH)
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Research Project (R01)
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Special Emphasis Panel (ZRG1-EMNR-K (02))
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Taymans, Susan
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University of Pennsylvania
Other Clinical Sciences
Schools of Veterinary Medicine
United States
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De La Fuente, Rabindranath; Baumann, Claudia; Viveiros, Maria M (2015) ATRX contributes to epigenetic asymmetry and silencing of major satellite transcripts in the maternal genome of the mouse embryo. Development 142:1806-17
Pattabiraman, Shrivatsav; Baumann, Claudia; Guisado, Daniela et al. (2015) Mouse BRWD1 is critical for spermatid postmeiotic transcription and female meiotic chromosome stability. J Cell Biol 208:53-69
El Zowalaty, A E; Baumann, C; Li, R et al. (2015) Seipin deficiency increases chromocenter fragmentation and disrupts acrosome formation leading to male infertility. Cell Death Dis 6:e1817
Baumann, Claudia; Olson, Mark; Wang, Kai et al. (2015) Arginine methyltransferases mediate an epigenetic ovarian response to endometriosis. Reproduction 150:297-310
Fayrer-Hosken, R; Stanley, A; Hill, N et al. (2012) Effect of Feeding Fescue Seed Containing Ergot Alkaloid Toxins on Stallion Spermatogenesis and Sperm Cells. Reprod Domest Anim :
De La Fuente, Rabindranath; Baumann, Claudia; Viveiros, Maria M (2012) Chromatin structure and ATRX function in mouse oocytes. Results Probl Cell Differ 55:45-68
De La Fuente, Rabindranath; Baumann, Claudia; Viveiros, Maria M (2011) Role of ATRX in chromatin structure and function: implications for chromosome instability and human disease. Reproduction 142:221-34
Baumann, Claudia; Daly, Christopher M; McDonnell, Sue M et al. (2011) Chromatin configuration and epigenetic landscape at the sex chromosome bivalent during equine spermatogenesis. Chromosoma 120:227-44
Baumann, Claudia; De La Fuente, Rabindranath (2011) Role of polycomb group protein cbx2/m33 in meiosis onset and maintenance of chromosome stability in the Mammalian germline. Genes (Basel) 2:59-80
Zeng, Wenxian; Baumann, Claudia; Schmidtmann, Anja et al. (2011) Lymphoid-specific helicase (HELLS) is essential for meiotic progression in mouse spermatocytes. Biol Reprod 84:1235-41

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