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.
Wu
Mei-Yi
MY
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas 77030, USA.
Tsai
Ting-Fen
TF
Beaudet
Arthur L
AL
D000483:Alleles; D000818:Animals; D000951:Antigens, Neoplasm / Q000235:genetics* / Q000502:physiology; D002352:Carrier Proteins / Q000235:genetics* / Q000502:physiology; D003433:Crosses, Genetic; D004268:DNA-Binding Proteins / Q000235:genetics / Q000502:physiology*; D004622:Embryo, Mammalian / Q000166:cytology; D044127:Epigenesis, Genetic; D018507:Gene Expression Regulation, Developmental; D018392:Genomic Imprinting; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D008957:Models, Genetic; D009363:Neoplasm Proteins / Q000235:genetics* / Q000502:physiology; D011401:Promoter Regions, Genetic; D017434:Protein Structure, Tertiary; D056465:Retinoblastoma-Binding Protein 1; D013234:Stem Cells / Q000166:cytology
C493892:ARID4B protein, human; D000951:Antigens, Neoplasm; C533431:Arid4a protein, mouse; D002352:Carrier Proteins; D004268:DNA-Binding Proteins; D009363:Neoplasm Proteins; C515305:Rbbp1l1 protein, mouse; D056465:Retinoblastoma-Binding Protein 1