Abstract
The α-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.
Highlights
Heterochromatin formation in eukaryotic cells is essential for the maintenance of nuclear architecture, the control of gene expression and chromosome segregation [1,2,3,4,5,6]
The a-thalassemia/ mental retardation X-linked protein (ATRX) is essential for the maintenance of chromosome stability during female meiosis
Our results provide direct evidence for a role of a-thalassemia/mental retardation X-linked protein (ATRX) in the regulation of pericentric heterochromatin structure and function in mammalian oocytes and have important implications for our understanding of the epigenetic factors contributing to the onset of aneuploidy in the female gamete
Summary
Heterochromatin formation in eukaryotic cells is essential for the maintenance of nuclear architecture, the control of gene expression and chromosome segregation [1,2,3,4,5,6]. Centric heterochromatin, is epigenetically determined by deposition of the histone variant CENP-A (centromere associated protein-A), contains several hundred kilobases of the 120 bp repeat unit of the minor satellite sequence and regulates the assembly of a single kinetochore on each sister chromatid required for microtubule attachment [9,10]. In several organisms including mammals, pericentric heterochromatin formation is essential to coordinate sister centromere cohesion and for the timely separation of individual chromatids during mitosis [2,3,7,10]. Members of the SWI/SNF2 protein family recruited to pericentric heterochromatin are essential to maintain sister chromatid cohesion until the onset of anaphase in order to ensure accurate chromosome segregation. While a growing body of evidence indicates that pericentric heterochromatin formation may have a significant impact on centromere cohesion during mitosis, little is known about this critical process during female mammalian meiosis
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