Loss of Maternal ATRX Results in Centromere Instability and Aneuploidy in the Mammalian Oocyte and Pre-Implantation Embryo

被引:77
作者
Baumann, Claudia [1 ]
Viveiros, Maria M. [2 ]
De la Fuente, Rabindranath [1 ]
机构
[1] Univ Penn, Dept Clin Studies, Female Germ Cell Biol Grp, Kennett Sq, PA USA
[2] Univ Penn, Sch Vet Med, Ctr Anim Transgenesis & Germ Cell Res, Kennett Sq, PA 19348 USA
来源
PLOS GENETICS | 2010年 / 6卷 / 09期
基金
美国国家卫生研究院;
关键词
HISTONE H3 PHOSPHORYLATION; CHROMATIN-REMODELING COMPLEX; MOUSE OOCYTES; CHROMOSOME CONDENSATION; PERICENTROMERIC HETEROCHROMATIN; SISTER CHROMATIDS; SYNDROME PROTEIN; TRANSGENIC RNAI; DNA METHYLATION; GENE-EXPRESSION;
D O I
10.1371/journal.pgen.1001137
中图分类号
Q3 [遗传学];
学科分类号
071007 ; 090102 ;
摘要
The alpha-thalassemia/mental retardation X-linked protein (ATRX) is a chromatin-remodeling factor known to regulate DNA methylation at repetitive sequences of the human genome. We have previously demonstrated that ATRX binds to pericentric heterochromatin domains in mouse oocytes at the metaphase II stage where it is involved in mediating chromosome alignment at the meiotic spindle. However, the role of ATRX in the functional differentiation of chromatin structure during meiosis is not known. To test ATRX function in the germ line, we developed an oocyte-specific transgenic RNAi knockdown mouse model. Our results demonstrate that ATRX is required for heterochromatin formation and maintenance of chromosome stability during meiosis. During prophase I arrest, ATRX is necessary to recruit the transcriptional regulator DAXX (death domain associated protein) to pericentric heterochromatin. At the metaphase II stage, transgenic ATRX-RNAi oocytes exhibit abnormal chromosome morphology associated with reduced phosphorylation of histone 3 at serine 10 as well as chromosome segregation defects leading to aneuploidy and severely reduced fertility. Notably, a large proportion of ATRX-depleted oocytes and 1-cell stage embryos exhibit chromosome fragments and centromeric DNA-containing micronuclei. Our results provide novel evidence indicating that ATRX is required for centromere stability and the epigenetic control of heterochromatin function during meiosis and the transition to the first mitosis.
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页数:15
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