RNA Induction and Inheritance of Epigenetic Cardiac Hypertrophy in the Mouse

• Published in: Developmental cell 2008-06, Vol.14 (6), p.962-969
• Main Authors: Wagner, Kay D., Wagner, Nicole, Ghanbarian, Hossein, Grandjean, Valérie, Gounon, Pierre, Cuzin, François, Rassoulzadegan, Minoo
• Format: Article
• Language: English
• Subjects: Animals; Biological and medical sciences; Body Weight; Cardiomegaly - genetics; Cardiomegaly - pathology; Cardiomegaly - physiopathology; Cell differentiation, maturation, development, hematopoiesis; Cell Nucleus - metabolism; Cell physiology; Cyclin-Dependent Kinase 9 - biosynthesis; Cyclin-Dependent Kinase 9 - ultrastructure; DEVBIO; Embryo, Mammalian - cytology; Embryo, Mammalian - embryology; Embryo, Mammalian - metabolism; Epididymis - cytology; Epigenesis, Genetic; Fundamental and applied biological sciences. Psychology; HUMDISEASE; Male; Mice; Mice, Mutant Strains; Microinjections; MicroRNAs - metabolism; Molecular and cellular biology; Mutation; Myocytes, Cardiac - metabolism; Myocytes, Cardiac - ultrastructure; Oligonucleotides - administration & dosage; Oligonucleotides - chemistry; Oocytes - metabolism; Organ Size - genetics; Phosphorylation; RNA; RNA - biosynthesis; RNA Polymerase II - metabolism; Spermatozoa - cytology
• ISSN: 1534-5807; 1878-1551
• DOI: 10.1016/j.devcel.2008.03.009

Epigenetic regulation shapes normal and pathological mammalian development and physiology. Our previous work showed that Kit RNAs injected into fertilized mouse eggs can produce heritable epigenetic defects, or paramutations, with relevant loss-of-function pigmentation phenotypes, which affect adult phenotypes in multiple succeeding generations of mice. Here, we illustrate the relevance of paramutation to pathophysiology by injecting fertilized mouse eggs with RNAs targeting Cdk9, a key regulator of cardiac growth. Microinjecting fragments of either the coding region or the related microRNA miR-1 led to high levels of expression of homologous RNA, resulting in an epigenetic defect, cardiac hypertrophy, whose efficient hereditary transmission correlated with the presence of miR-1 in the sperm nucleus. In this case, paramutation increased rather than decreased expression of Cdk9. These results highlight the diversity of RNA-mediated epigenetic effects and may provide a paradigm for clinical cases of familial diseases whose inheritance is not fully explained in Mendelian terms.