H19acts as a trans regulator of the imprinted gene network controlling growth in mice

Abstract

The imprinted H19 gene produces a non-coding RNA of unknown function. Mice lacking H19 show an overgrowth phenotype, due to a cis effect of the H19 locus on the adjacent Igf2 gene. To explore the function of the RNA itself, we produced transgenic mice overexpressing H19. We observed postnatal growth reduction in two independent transgenic lines and detected a decrease of Igf2 expression in embryos. An extensive analysis of several other genes from the newly described imprinted gene network (IGN) was performed in both loss-and gain-of-function animals. We found that H19 deletion leads to the upregulation of several genes of the IGN. This overexpression is restored to the wild-type level by transgenic expression of H19. We therefore propose that the H19 gene participates as a trans regulator in the fine-tuning of this IGN in the mouse embryo. This is the first in vivo evidence of a functional role for the H19 RNA. Our results also bring further experimental evidence for the existence of the IGN and open new perspectives in the comprehension of the role of genomic imprinting in embryonic growth and in human imprinting pathologies.

Characterization of multi-locus imprinting disturbances and underlying genetic defects in patients with chromosome 11p15.5 related imprinting disorders

“…According, recent advances sustain an interplay among ICR1 and other iDMRs (our unpublished data) and chromatin interactions between H19 and portions of chromosome 7 [34]. MEST methylation may also be part of an imprinting gene network (IGN), involving the trans -acting functions of H19 lncRNA [35,36]. Further investigations are requested to better elucidate this finding.…”

Imprinted gene expression in hybrids: perturbed mechanisms and evolutionary implications

“…ZAC1 binds to regulatory sequences at these other loci, and its expression was proposed to be important in the control of an imprinted gene network (Varrault et al, 2006). Further evidence for interdependence of imprinted gene expression comes from targeting studies on the H19 gene (Gabory et al, 2009) and from data indicating that the imprinted IGF2-H19 locus physically interacts with several other imprinted loci in the nucleus (Murrell et al, 2004;Zhao et al, 2006). Genetic studies on Peg3 using congenic lines formally showed that its frequently observed loss of imprinting in (MU Â S)F 1 hybrids is due to a yet unknown spretus-specific trans-acting factor (Shi et al, 2005).…”

Evolution of genomic imprinting as a coordinator of coadapted gene expression

“…For example, the IGN includes at least 16 imprinted genes that tend to be coexpressed and show coordinated changes in response to differentiation (41), mutation (e.g., knockout of H19 leads to upregulation of several members of the IGN, ref. 42), and in vitro manipulation (e.g., in vitro fertilization disrupts patterns of methylation at specific sites within the H19-Igf2 (insulin-like growth factor 2) locus, and these disruptions appear to be compensated for through the IGN, ref. 43).…”