The expression of a subset of genes in mammals is affected by parental origin. These genes, which are designated as imprinted, are expressed from a single parental allele. The existence of imprinted genes is hypothesized to explain why nuclear contributions from both parents are required for normal mammalian development. Furthermore, imprinting plays a role in the transmission of a number of human genetic diseases, including Beckwith-Wiedemann Syndrome, Prader-Willi Syndrome and Angelman Syndrome, in that the sex of the parent that transmits the affected gene(s) determines whether the child will develop the disease. Although greater than 75 imprinted genes have been identified and some of the sequences that mediate their imprinting defined, much less is known about the trans-acting factors that govern imprinted gene expression. These factors are required to establish and maintain imprints, as well as provide long-term stability and memory for the imprints. In this proposal, we will focus on the role of candidate trans-acting factors that likely serve as epigenetic regulators in imprint establishment and maintenance.
Specific Aim 1 will examine the general role of the multi-functional protein CTCF, which provides enhancer blocking function and a DNA methylation-free region on the imprinting control region (ICR) of the H19/Igf2 locus. Using CTCF-depleted preimplantation mouse embryos, we will investigate the consequences for imprinting regulation of H19 and other imprinted genes postulated to be regulated by CTCF.
Specific Aim 2 will assess the requirement for proteins that bind to methylated CpG dinucleotides, with the hypothesis that these methyl CpG binding proteins are essential to maintaining imprinted gene expression and differential methylation of ICRs of a large number of imprinted genes. Last, Specific Aim 3 will determine whether the EED Polycomb Group protein is required for the establishment of genomic imprinting in the early embryo. Together these experiments will provide a greater understanding of the mechanism of genomic imprinting in early mouse embryos and new insights into the etiology of the loss of imprinting mutations observed in various imprinting syndromes including Beckwith-Wiedemann, Prader-Willi, Angelman and Silver-Russell Syndromes. The proposed studies will provide new information regarding the mechanism by which genomic imprinting is established and maintained in mouse oocytes and embryos. The results of these studies will also impact our understanding of the loss of imprinting and DNA methylation mutations observed in various human imprinting syndromes including Beckwith-Wiedemann, Prader-Willi, Angelman and Silver-Russell Syndromes.
|Plasschaert, Robert N; Vigneau, Sébastien; Tempera, Italo et al. (2014) CTCF binding site sequence differences are associated with unique regulatory and functional trends during embryonic stem cell differentiation. Nucleic Acids Res 42:774-89|
|Weaver, Jamie R; Bartolomei, Marisa S (2014) Chromatin regulators of genomic imprinting. Biochim Biophys Acta 1839:169-77|
|Abramowitz, Lara K; Bartolomei, Marisa S (2012) Genomic imprinting: recognition and marking of imprinted loci. Curr Opin Genet Dev 22:72-8|
|Deng, Zhong; Wang, Zhuo; Stong, Nick et al. (2012) A role for CTCF and cohesin in subtelomere chromatin organization, TERRA transcription, and telomere end protection. EMBO J 31:4165-78|
|Lin, Shu; Ferguson-Smith, Anne C; Schultz, Richard M et al. (2011) Nonallelic transcriptional roles of CTCF and cohesins at imprinted loci. Mol Cell Biol 31:3094-104|
|Bartolomei, Marisa S; Ferguson-Smith, Anne C (2011) Mammalian genomic imprinting. Cold Spring Harb Perspect Biol 3:|
|Ma, Pengpeng; Lin, Shu; Bartolomei, Marisa S et al. (2010) Metastasis tumor antigen 2 (MTA2) is involved in proper imprinted expression of H19 and Peg3 during mouse preimplantation development. Biol Reprod 83:1027-35|
|Weaver, Jamie R; Susiarjo, Martha; Bartolomei, Marisa S (2009) Imprinting and epigenetic changes in the early embryo. Mamm Genome 20:532-43|
|Bartolomei, Marisa S (2009) Genomic imprinting: employing and avoiding epigenetic processes. Genes Dev 23:2124-33|
|Essien, Kobby; Vigneau, Sebastien; Apreleva, Sofia et al. (2009) CTCF binding site classes exhibit distinct evolutionary, genomic, epigenomic and transcriptomic features. Genome Biol 10:R131|
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