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Deficiency of Rbbp1/Arid4a and Rbbp1l1/Arid4b alters epigenetic modifications and suppresses an imprinting defect in the PWS/AS domain

¹ Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas 77030, USA; ² Department of Life Science and Institute of Genetics, National Yang-Ming University, Taipei 112, Taiwan

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.

[Keywords: Rbbp1/Arid4a ; Rbbp1l1/Arid4b ; Prader-Willi/Angelman domain; genomic imprinting; epigenetic modifications]

Received May 25, 2006; revised version accepted August 28, 2006.

E-MAIL abeaudet{at}bcm.tmc.edu; FAX (713) 798-7773.

Article is online at http://www.genesdev.org/cgi/doi/10.1101/gad.1452206.

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