Mouse imprinting defect mutations that model Angelman syndrome

Wu, Mei Yi; Chen, Ken Shiung; Bressler, Jan; Hou, Aihua; Tsai, Ting Fen; Beaudet, Arthur L.

doi:10.1002/gene.20179

Cited by 28 publications

(36 citation statements)

References 37 publications

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“…Although all nine repeats are unlikely to be active promoters, it is clear that some are used in both oocytes and somatic cells (10,(18)(19)(20)32). Removal of the three proximal promoters leads to a weak partial imprinting defect, consistent with functional complementation by the remaining upstream promoters (33). Conversely, BAC transgenes bearing only the three proximal promoters generate sufficient transcripts for efficient imprinting (20).…”

Section: Discussionmentioning

confidence: 94%

Angelman syndrome imprinting center encodes a transcriptional promoter

Lewis

Brant

Kramer

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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Clusters of imprinted genes are often controlled by an imprinting center that is necessary for allele-specific gene expression and to reprogram parent-of-origin information between generations. An imprinted domain at 15q11–q13 is responsible for both Angelman syndrome (AS) and Prader–Willi syndrome (PWS), two clinically distinct neurodevelopmental disorders. Angelman syndrome arises from the lack of maternal contribution from the locus, whereas Prader–Willi syndrome results from the absence of paternally expressed genes. In some rare cases of PWS and AS, small deletions may lead to incorrect parent-of-origin allele identity. DNA sequences common to these deletions define a bipartite imprinting center for the AS–PWS locus. The PWS–smallest region of deletion overlap (SRO) element of the imprinting center activates expression of genes from the paternal allele. The AS–SRO element generates maternal allele identity by epigenetically inactivating the PWS–SRO in oocytes so that paternal genes are silenced on the future maternal allele. Here we have investigated functional activities of the AS–SRO, the element necessary for maternal allele identity. We find that, in humans, the AS–SRO is an oocyte-specific promoter that generates transcripts that transit the PWS–SRO. Similar upstream promoters were detected in bovine oocytes. This result is consistent with a model in which imprinting centers become DNA methylated and acquire maternal allele identity in oocytes in response to transiting transcription.

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Section: Discussionmentioning

confidence: 94%

Angelman syndrome imprinting center encodes a transcriptional promoter

Lewis

Brant

Kramer

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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“…Using DNA derived from the offspring for methylation analysis of the Snrpn and Ndn CpG islands by Southern blotting, mice inheriting only the AS-IC an mutation had an absence of methylation on both alleles for Snrpn and reduced methylation of DNA at the Ndn locus (Fig. 6A, mouse 5) as previously reported (Wu et al 2006). Interestingly, transmission of both the AS-IC an and Arid4b mutations to double-heterozygous offspring demonstrated an approximately equal intensity of methylated and unmethylated fragments at Snrpn and Ndn CpG islands (Fig.…”

Section: Mutations Of Arid4a Arid4b or Rb Suppressed An As-ic Imprimentioning

confidence: 60%

“…Although a murine equivalent to the human AS-IC has not yet been identified, we have recently reported a mouse model of an AS imprinting defect with the AS-IC an mutation (Wu et al 2006). To further investigate the roles of Arid4a and Arid4b in the regulation of imprinting for the PWS/AS region, we examined the genetic interaction of these two genes with the AS-IC by mating female mice with the AS-IC an mutation to male mice carrying the Arid4a or Arid4b mutations (Fig.…”

Section: Mutations Of Arid4a Arid4b or Rb Suppressed An As-ic Imprimentioning

confidence: 99%

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

Wu¹,

Tsai²,

Beaudet³

2006

Genes Dev.

Self Cite

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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.

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“…AS (8) 3 insertion/duplication located 13 kb upstream of Snrpn exon 1 AS imprinting mutation (9) 4 80-kb deletion located upstream of Snrpn exon 1 AS imprinting mutation (9) 5 Ube3a-Gabrb3 -Atp10a deletion AS (10) and Cy5 for the labelling of wild type and diseased samples prevented labelling bias. In the labelling reaction, the ratio of "dye: protein" was kept low to ensure optimal labelling efficiency.…”

Section: Mutationmentioning

confidence: 99%