Activation of paternally expressed genes and perinatal death caused by deletion of the Gtl2 gene.
The Dlk1-Gtl2 imprinting locus is located on mouse distal chromosome 12 and consists of multiple maternally expressed non-coding RNAs and several paternally expressed protein-coding genes. The imprinting of this locus plays a crucial role in embryonic development and postnatal growth. At least one cis-element, the intergenic differentially methylated region (IG-DMR) is required for expression of maternally expressed genes and repression of silenced paternally expressed genes. The mechanism by which the IG-DMR functions is largely unknown. However, it has been suggested that the unmethylated IG-DMR acts as a positive regulator activating expression of non-coding RNAs. Gtl2 is the first non-coding RNA gene downstream of the IG-DMR. Although its in vivo function in the mouse is largely unknown, its human ortholog MEG3 has been linked to tumor suppression in human tumor-derived cell lines. We generated a knockout mouse model, in which the first five exons and adjacent promoter region of the Gtl2 gene were deleted. Maternal deletion of Gtl2 resulted in perinatal death and skeletal muscle defects, indicating that Gtl2 plays an important role in embryonic development. The maternal deletion also completely abolished expression of downstream maternally expressed genes, activated expression of silenced paternally expressed genes and resulted in methylation of the IG-DMR. By contrast, the paternal inherited deletion did not have this effect. These data strongly indicate that activation of Gtl2 and its downstream maternal genes play an essential role in regulating Dlk1-Gtl2 imprinting, possibly by maintaining active status of the IG-DMR.
Zhou
Yunli
Y
Massachusetts General Hospital, Boston, MA 02114, USA. yzhou2@partners.org
Cheunsuchon
Pornsuk
P
Nakayama
Yuki
Y
Lawlor
Michael W
MW
Zhong
Ying
Y
Rice
Kimberley A
KA
Zhang
Li
L
Zhang
Xun
X
Gordon
Francesca E
FE
Lidov
Hart G W
HG
Bronson
Roderick T
RT
Klibanski
Anne
A
D000483:Alleles; D000818:Animals; D001483:Base Sequence; D002135:Calcium-Binding Proteins; D019175:DNA Methylation; D005260:Female; D017353:Gene Deletion; D018507:Gene Expression Regulation, Developmental; D020868:Gene Silencing; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D046529:Microscopy, Electron, Transmission; D018482:Muscle, Skeletal / Q000196:embryology / Q000378:metabolism / Q000648:ultrastructure; D010920:Placenta / Q000378:metabolism; D010929:Placentation; D011247:Pregnancy; D011506:Proteins / Q000235:genetics / Q000378:metabolism*; D062085:RNA, Long Noncoding
D002135:Calcium-Binding Proteins; C512925:Dlk1 protein, mouse; D036341:Intercellular Signaling Peptides and Proteins; C422882:MEG3 non-coding RNA, mouse; D011506:Proteins; D062085:RNA, Long Noncoding