RNA Induction and Inheritance of Epigenetic Cardiac Hypertrophy in the Mouse

Abstract

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.

Role of microRNAs in cardiac hypertrophy and heart failure

“…2). Wagner et al recently injected the fragments of either the coding region or the related microRNA miR-1 into fertilized mouse eggs (25). This microinjecting led to high levels of expression of homologous RNA, resulting in an epigenetic defect, cardiac hypertrophy.…”

Epigenetics and developmental programming of welfare and production traits in farm animals

“…It follows that much of our knowledge of transgenerational epigenetic inheritance in mammals pertains largely to inbred mice, where maternally or paternally induced transmission can come in the form of covalent modifications to DNA and histone methylation (e.g. Padmanabhan et al 2013;Wei et al 2014;Siklenka et al 2015) and altered RNA expression (Wagner et al 2008), often in a breeding scheme-dependent manner (Yuan et al 2015). Not surprisingly, evidence for similar effects occurring in long-lived and out-bred farm animals is scarce, leading González-Recio et al (2015) to question its importance in livestock production.…”

Interindividual Variation in DNA Methylation at a Putative POMC Metastable Epiallele Is Associated with Obesity

“…Our data also point to the influence of some other factor transmitted from the father to the offspring, although the mechanism is unknown. One possibility is the transmission of sperm micro-RNAs (Gapp et al, 2014;Wagner et al, 2008).…”