H19 gene expression is up-regulated exclusively by stabilization of the RNA during muscle cell differentiation

H19 is a paternally imprinted gene whose expression produces a 2.4 kb RNA i n most tissues during development and in mammalian myoblastic cell lines up on differentiation. Deletion of the active maternal allele of H19 and its f lanking regions in the mouse leads to biallelic methylation and loss of imp rinting of the neighbouring Igf2 gene, The function of H19 RNA remains unkn own and, although polysome-associated, the absence of a conserved open read ing frame suggests that it does not encode a protein product. We describe a novel post-transcriptional regulation of H19 gene expression which,in spit e of this lack of coding capacity, is dependent on translational activity. We show that stabilization of the RNA is solely responsible for its accumul ation during in vitro muscle cell differentiation, This conclusion is based on the finding that inhibition of protein synthesis results in a dramatic destabilization of H19 RNA in proliferating mouse C2C12 myoblastic cells bu t not in differentiated cells, and on run-on experiments which showed that the rate of transcription of H19 RNA remains constant during muscle cell di fferentiation. This mechanism could also be involved in H19 gene expression during mouse development in addition to its transcriptional activation whi ch we have shown to occur.