H19 (gene) - RNA Product

RNA Product

The H19 gene codes for a 2.3 kb RNA product. It is transcribed by RNA polymerase II, spliced and polyadenylated, but it does not appear to be translated.

After many studies, researchers finally concluded that the end product of the H19 gene is a RNA strand for the following reasons:

• The H19 RNA product is evolutionarily conserved at the nucleotide level in humans and rodents
• There is no known open reading frame; the H19 mRNA contains stop codons in all 3 reading frames
• The cDNA version of the human H19 does not contain the short introns that are characteristic of imprinted genes
• Although the RNA sequence was highly conserved evolutionarily, at the amino acid level, there was a complete absence of conservation
• Free energy (thermodynamics) analysis of the H19 RNA sequence revealed a multitude of possible secondary RNA structures, including 16 helices and various hairpin loops
• In situ hybridization of the H19 RNA revealed that it localizes in a cytoplasmic ribonucleoprotein particle, leading some to suggest that the H19 RNA functions as a riboregulator.

Loss of function and overexpression experiments on H19 have revealed two things:

1. Loss of H19 is not lethal in mice
2. Overexpression of H19 is a dominant and lethal mutation

Mice with a loss of H19 function express an overgrowth phenotype similar to babies with BWS. This has led researchers to suggest that perhaps the only function of H19 RNA expression is to regulate the expression of IGF2 (Insulin Growth Factor 2). Overexpression of IGF2 can be responsible for overgrowth, and generally, IGF2 is expressed in the absence of H19. Mouse embryos overexpressing H19 tend to die between embryonic day 14 and birth. Brunkow et al. have suggested two reasons for the lethality of H19 overexpression in embryonic mice:

1. The overexpression of H19 in tissues where it is normally expressed (e.g., liver and gut) caused its lethal effects
   • This implies that H19 gene dosage is under strict control in the fetus
2. The expression of H19 in tissues where it is normally not expressed (e.g., brain) caused its lethal effects