Rescue of placental phenotype in a mechanistic model of Beckwith-Wiedemann syndrome.
BACKGROUND
Several imprinted genes have been implicated in the process of placentation. The distal region of mouse chromosome 7 (Chr 7) contains at least ten imprinted genes, several of which are expressed from the maternal homologue in the placenta. The corresponding paternal alleles of these genes are silenced in cis by an incompletely understood mechanism involving the formation of a repressive nuclear compartment mediated by the long non-coding RNA Kcnq1ot1 initiated from imprinting centre 2 (IC2). However, it is unknown whether some maternally expressed genes are silenced on the paternal homologue via a Kcnq1ot1-independent mechanism. We have previously reported that maternal inheritance of a large truncation of Chr7 encompassing the entire IC2-regulated domain (DelTel7 allele) leads to embryonic lethality at mid-gestation accompanied by severe placental abnormalities. Kcnq1ot1 expression can be abolished on the paternal chromosome by deleting IC2 (IC2KO allele). When the IC2KO mutation is paternally inherited, epigenetic silencing is lost in the region and the DelTel7 lethality is rescued in compound heterozygotes, leading to viable DelTel7/IC2KO mice.


RESULTS
Considering the important functions of several IC2-regulated genes in placentation, we set out to determine whether these DelTel7/IC2KO rescued conceptuses develop normal placentae. We report no abnormalities with respect to the architecture and vasculature of the DelTel7/IC2KO rescued placentae. Imprinted expression of several of the IC2-regulated genes critical to placentation is also faithfully recapitulated in DelTel7/IC2KO placentae.


CONCLUSIONS
Taken together, our results demonstrate that all the distal chromosome 7 imprinted genes implicated in placental function are silenced by IC2 and Kcnq1ot1 on the paternal allele. Furthermore, our results demonstrate that the methylated maternal IC2 is not required for the regulation of nearby genes. The results show the potential for fully rescuing LQ trans placental abnormalities that are caused by imprinting defects.
Oh-McGinnis
Rosemary
R
Department of Medical Genetics, Molecular Epigenetics Group, Life Sciences Institute, University of British Columbia, Vancouver, Canada.
Bogutz
Aaron B
AB
Lee
Kang Yun
KY
Higgins
Michael J
MJ
Lefebvre
Louis
L
D000818:Animals; D001506:Beckwith-Wiedemann Syndrome / Q000235:genetics* / Q000517:prevention & control; D033481:Chromosomes, Mammalian; D005260:Female; D018392:Genomic Imprinting; D006801:Humans; D051657:KCNQ1 Potassium Channel / Q000235:genetics; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D010920:Placenta / Q000002:abnormalities* / Q000378:metabolism*; D011247:Pregnancy; D022661:RNA, Untranslated / Q000378:metabolism
D051657:KCNQ1 Potassium Channel; C496910:Kcnq1 protein, mouse; D022661:RNA, Untranslated
Hum Mol Genet. 1998 Mar;7(3):483-7
9467008
Placenta. 2006 Aug;27(8):882-8
16269175
Dev Cell. 2008 Nov;15(5):668-79
18848501
Hum Mol Genet. 1998 Jul;7(7):1149-59
9618174
Methods Mol Med. 2006;121:371-92
16251755
Physiology (Bethesda). 2005 Jun;20:180-93
15888575
Nat Genet. 2004 Aug;36(8):818-26
15273686
Nat Genet. 1996 Oct;14(2):171-3
8841187
BMC Dev Biol. 2007 May 21;7:53
17517131
Genes Dev. 1988 Dec;2(12A):1639-46
3215514
Hum Mol Genet. 2001 Jul 15;10(15):1601-9
11468278
Obstet Gynecol. 1994 May;83(5 Pt 2):813-7
8159359
Science. 1999 Apr 9;284(5412):330-3
10195900
Biol Reprod. 2003 Jan;68(1):40-4
12493693
Nucleic Acids Res. 2006 Jul 19;34(12):e88
16855283
Dev Biol. 2002 Oct 15;250(2):358-73
12376109
Nat Genet. 2002 Nov;32(3):426-31
12410230
Hum Mol Genet. 2000 Nov 1;9(18):2691-706
11063728
Trends Genet. 2005 Aug;21(8):457-65
15990197
Nature. 1994 Sep 22;371(6495):333-6
8090202
Hum Mol Genet. 1997 Nov;6(12):2021-9
9328465
Nature. 2007 May 24;447(7143):425-32
17522676
Nature. 1996 Jan 11;379(6561):131-7
8538762
Hum Mol Genet. 2005 Feb 15;14(4):503-11
15640248
Cytogenet Genome Res. 2006;113(1-4):90-8
16575167
Genes Dev. 2001 Sep 15;15(18):2361-6
11562346
Hum Mol Genet. 2001 Dec 15;10(26):2989-3000
11751681
Nature. 1997 May 8;387(6629):151-8
9144284
BMC Dev Biol. 2007 Mar 06;7:14
17341302
Fetal Pediatr Pathol. 2009;28(1):9-23
19116812
Mol Cell Biol. 1998 Jun;18(6):3466-74
9584186
Hum Mol Genet. 2000 Jul 22;9(12):1829-41
10915772
Mol Cell Biol. 2007 Apr;27(7):2636-47
17242189
Proc Natl Acad Sci U S A. 2006 Apr 25;103(17):6623-8
16614068
Genes Dev. 1997 Apr 15;11(8):973-83
9136926
J Clin Invest. 2000 Feb;105(3):247-52
10675349
EMBO J. 2008 Jan 9;27(1):168-78
18079696
Nature. 1997 Oct 23;389(6653):809-15
9349812
Nat Genet. 2004 Dec;36(12):1291-5
15516931
Nat Genet. 1998 Oct;20(2):163-9
9771709
J Med Genet. 2003 Nov;40(11):797-801
14627666
Placenta. 2008 May;29(5):454-60
18342934
J Biochem. 2000 Jan;127(1):73-83
10731669
Hum Mol Genet. 1998 Apr;7(4):597-608
9499412
Nat Genet. 2004 Dec;36(12):1296-300
15516932
Genes Dev. 2006 May 15;20(10):1268-82
16702402
Mol Cell Biol. 2008 Feb;28(3):1092-103
18039841
Mech Dev. 2004 Oct;121(10):1199-210
15327781
BMC Genomics. 2008 Jul 28;9:352
18662396
Proc Natl Acad Sci U S A. 2002 May 28;99(11):7490-5
12032310
Nat Genet. 1995 Mar;9(3):235-42
7773285
J Assist Reprod Genet. 2002 May;19(5):240-4
12099555
Methods Mol Med. 2006;121:275-93
16251749