Faculty Collaboration Database

Activation of paternally expressed genes and perinatal death caused by deletion of the Gtl2 gene. Development 2010 Aug;137(16):2643-52

Date

07/09/2010

Pubmed ID

20610486

Pubmed Central ID

PMC2910384

DOI

10.1242/dev.045724

Scopus ID

2-s2.0-77955744813 (requires institutional sign-in at Scopus site)   122 Citations

Abstract

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.

Author List

Zhou Y, Cheunsuchon P, Nakayama Y, Lawlor MW, Zhong Y, Rice KA, Zhang L, Zhang X, Gordon FE, Lidov HG, Bronson RT, Klibanski A

Author

Michael W. Lawlor MD, PhD Adjunct Professor in the Pathology department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Alleles
Animals
Base Sequence
Calcium-Binding Proteins
DNA Methylation
Female
Gene Deletion
Gene Expression Regulation, Developmental
Gene Silencing
Intercellular Signaling Peptides and Proteins
Male
Mice
Mice, Inbred C57BL
Mice, Knockout
Microscopy, Electron, Transmission
Muscle, Skeletal
Placenta
Placentation
Pregnancy
Proteins
RNA, Long Noncoding