Loss of imprinting mutations define both distinct and overlapping roles for misexpression of IGF2 and of H19 lncRNA.
Nucleic Acids Res
; 45(22): 12766-12779, 2017 Dec 15.
Article
in En
| MEDLINE
| ID: mdl-29244185
ABSTRACT
Imprinted genes occur in discrete clusters that are coordinately regulated by shared DNA elements called Imprinting Control Regions. H19 and Igf2 are linked imprinted genes that play critical roles in development. Loss of imprinting (LOI) at the IGF2/H19 locus on the maternal chromosome is associated with the developmental disorder Beckwith Wiedemann Syndrome (BWS) and with several cancers. Here we use comprehensive genetic and genomic analyses to follow muscle development in a mouse model of BWS to dissect the separate and shared roles for misexpression of Igf2 and H19 in the disease phenotype. We show that LOI results in defects in muscle differentiation and hypertrophy and identify primary downstream targets Igf2 overexpression results in over-activation of MAPK signaling while loss of H19 lncRNA prevents normal down regulation of p53 activity and therefore results in reduced AKT/mTOR signaling. Moreover, we demonstrate instances where H19 and Igf2 misexpression work separately, cooperatively, and antagonistically to establish the developmental phenotype. This study thus identifies new biochemical roles for the H19 lncRNA and underscores that LOI phenotypes are multigenic so that complex interactions will contribute to disease outcomes.
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Beckwith-Wiedemann Syndrome
/
Insulin-Like Growth Factor II
/
Genomic Imprinting
/
RNA, Long Noncoding
/
Mutation
Type of study:
Prognostic_studies
Limits:
Animals
/
Humans
Language:
En
Journal:
Nucleic Acids Res
Year:
2017
Document type:
Article
Affiliation country:
United States