The mouse gene H19 is the first reported as Long non-coding RNA by (Brannan C.I et al., 1990), The group showed despite the fact that this gene is transcribed by RNA polymerase-II and is spliced and polyadenylated like any other mRNA, H19 RNA is “not a classical mRNA”. Instead, the product of this unusual gene may be an RNA molecule.

H19 gene was first identified in a screen of fetal liver cDNA library to find the genes that were coordinately regulated with the AFP (Alpha Feto Protein) gene. The AFP gene is located on the q arm of chromosome 4 (4q25). AFP is the most abundant plasma protein found in the human fetus. Plasma levels decrease rapidly after birth but begin decreasing prenatally starting at the end of the first trimester. Normal adult levels are usually achieved by the age of 8 to 12 months.

Pachnis V et al. 1984, found that the levels of alpha fetoprotein in mice are determined by at least  two trans-acting, unlinked genes, raf and rif. raf determines the basal levels of a-fetoprotein mRNA in adult mice, while Rif determines its degree of inducibility during liver regeneration. To determine whether these regulatory loci affect other structural genes, the screened a murine fetal liver cDNA library for clones containing mRNA sequences that decrease after birth. One such clone, termed pHl9, was identified, and its mRNA was shown to be under the control of both raf and Rif. The single-copy gene for H19 “mRNA” was localized to chromosome 7.

In 1990 Brannan C.I et al., found H19 gene was expressed at high levels in fetal and neonatal liver, and its 600-fold repression in the adult was under the control of raf. Sequence analysis of the single-copy H19 gene revealed the presence of multiple small open reading frames (ORFs), none of which spanned more than two of its five exons. The largest of these, called ORF5 was located entirely within the first exon and could potentially encode a 132-amino-acid protein. This ORF begins 680 bases downstream of the cap site and is preceded by four small ORFs, the largest of which could encode a protein of 27 amino acids. As there was no precedent for such a gene organization and hence the group decided to investigate.

And found H19 It shares features common to other mRNAs: it is transcribed by RNA polymerase II, processed by RNA splicing, and polyadenylated. Unlike mRNAs, it is not associated with ribosomes in any tissue or at any stage in development that was examined. They concluded from the findings that the RNA is never translated and even if H19 RNA functions as a mRNA, then it must be under stringent translational control. However they considered H19 gene functions as an RNA molecules, hence it was the first large non-coding RNA.

Shortly afterwords another non-coding (second) was found to be expressed exclusively from the inactive X chromosome and later demonstrated to be required for X inactivation in mammals and termed as XIST lncRNA.