Deficiency of Rbbp1/Arid4a and Rbbp1l1/Arid4b alters epigenetic modifications and suppresses an imprinting defect in the PWS/AS domain.
Prader-Willi syndrome (PWS) and Angelman syndrome (AS) are caused by deficiency of imprinted gene expression from paternal or maternal chromosome 15q11-q13, respectively. Genomic imprinting of the PWS/AS domain is regulated through a bipartite cis-acting imprinting center (PWS-IC/AS-IC) within and upstream of the SNRPN promoter. Here, we show that two Rb-binding ... protein-related genes, Rbbp1/Arid4a and Rbbp1l1/Arid4b, are involved in the regulation of imprinting of the IC. We recovered these two genes from gene trap mutagenesis selecting for altered expression of an Snrpn-EGFP fusion gene strategy. RBBP1/ARID4A is an Rb-binding protein. RBBP1/ARID4A interacts with RBBP1L1/ARID4B and with the Snrpn promoter, implying that both are part of a protein complex. To further elucidate their roles on regulation of imprinting, we deleted the Rbbp1/Arid4a and Rbbp1l1/Arid4b genes in mice. Combined homozygous deficiency for Rbbp1/Arid4a and heterozygous deficiency for Rbbp1l1/Arid4b altered epigenetic modifications at the PWS-IC with reduced trimethylation of histone H4K20 and H3K9 and reduced DNA methylation, changing the maternal allele toward a more paternal epigenotype. Importantly, mutations of Rbbp1/Arid4a, Rbbp1l1/Arid4b, or Rb suppressed an AS imprinting defect caused by a mutation at the AS-IC. These data identify Rbbp1/Arid4a and Rbbp1l1/Arid4b as new members of epigenetic complexes regulating genomic imprinting at the PWS/AS domain.
Mesh Terms:
Alleles, Animals, Antigens, Neoplasm, Carrier Proteins, Crosses, Genetic, DNA-Binding Proteins, Embryo, Mammalian, Epigenesis, Genetic, Gene Expression Regulation, Developmental, Genomic Imprinting, Humans, Mice, Mice, Transgenic, Models, Genetic, Neoplasm Proteins, Promoter Regions, Genetic, Protein Structure, Tertiary, Retinoblastoma-Binding Protein 1, Stem Cells
Alleles, Animals, Antigens, Neoplasm, Carrier Proteins, Crosses, Genetic, DNA-Binding Proteins, Embryo, Mammalian, Epigenesis, Genetic, Gene Expression Regulation, Developmental, Genomic Imprinting, Humans, Mice, Mice, Transgenic, Models, Genetic, Neoplasm Proteins, Promoter Regions, Genetic, Protein Structure, Tertiary, Retinoblastoma-Binding Protein 1, Stem Cells
Genes Dev.
Date: Oct. 15, 2006
PubMed ID: 17043311
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