Centromeric heterochromatin formation is essential to regulate fundamental aspects of nuclear architecture, gene silencing through DNA methylation, and chromosome segregation. The appropriate regulation of these processes is critical for the successful completion of oogenesis. Although the mechanisms involved in the establishment of heterochromatin domains during oogenesis are currently unknown, chromatin-remodeling proteins are likely to be important determinants. The focus of this proposal will be on ATRX, a member of the SWI/SNF2 family of chromatin remodeling proteins. This proposal is based on the hypotheses that: 1) chromatin remodeling proteins such as ATRX are important components of centromeric heterochromatin domains in mammalian oocytes; 2) that ATRX is essential for proper chromosome segregation during meiosis; and 3) that binding of ATRX to centromeric domains is essential for DNA methylation at satellite centromeric sequences. The specific objectives include: (1) The functional characterization of the ATRX protein in mouse oocytes; (2) To determine the mechanisms by which ATRX is bound to centromeric heterochromatin during oogenesis; (3) To determine whether ATRX is involved in establishing the patterns of DNA methylation at centromeric satellite sequences during the transition from meiosis to the first mitosis. A transgenic RNA interference (RNAi) approach will be used to generate an oocyte-specific conditional knockdown of the ATRX transcript. This mouse model will be used to establish whether functional ablation of ATRX disrupts appropriate chromosome-microtubule interactions during meiosis and the transition from gamete to embryo. Moreover, whether ATRX is involved in methylation of minor or major satellite DNA sequences will be determined. These studies will provide new information regarding the relationship between DNA methylation, heterochromatin formation and chromosome segregation during female meiosis, as well as the role of meiotic centromere function in the transmission of a euploid chromosome complement.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Research Project (R01)
Project #
1R01HD042740-01A2
Application #
6821250
Study Section
Reproductive Biology Study Section (REB)
Program Officer
Taymans, Susan
Project Start
2004-07-01
Project End
2007-06-30
Budget Start
2004-07-01
Budget End
2005-06-30
Support Year
1
Fiscal Year
2004
Total Cost
$285,300
Indirect Cost
Name
University of Pennsylvania
Department
Other Clinical Sciences
Type
Schools of Veterinary Medicine
DUNS #
042250712
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
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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