# H19--A MODEL FOR PARENTAL IMPRINTING IN THE MOUSE

> **NIH NIH R01** · PRINCETON UNIVERSITY · 1994 · $238,354

## Abstract

The purpose of this application is to investigate the function and
mechanisms of parental imprinting in mammals, using as a model system the
murine Igf2 and H19 genes. Igf2 encodes the fetal-specific growth factor
insulin-like growth factor II, and is expressed throughout development
primarily from the paternally inherited chromosome. The closely linked H19
gene is expressed in a very similar pattern to Igf2, but exclusively from
the maternal chromosome. The imprinting and linkage of these genes is
conserved in humans, where disruptions in their gene dosage have been
implicated in Beckwith-Wiedeman syndrome, Wilm's tumor and susceptibility
to childhood tumors such as rhabdomyosarcomas and hepatocellular
carcinomas. A series of mutations will be generated in mice to test the
role of these genes in these disorders. The first specific aim is to test
a model to explain the reciprocal imprinting of Igf2 and H19. The model
proposes that the genes compete in cis for common regulatory elements. The
competition is biased differently on the two chromosomes by the presence
of paternal-specific DNA methylation, which acts to silence the H19
promoter and facilitate Igf2 transcription. Experiments are proposed to
test the role of specific enhancers which lie 3' to the H19 gene by
mutating them via homologous recombination in embryonic stem cells. The
effects of both maternal and paternal inheritance of the deletion of the
enhancers on Igf2 and H19 will be examined.  The basis for the
preferential transcription of H19 on the apparently unmarked maternal
chromosome will be investigated by transfecting both wild type and mutant
yeast artificial chromosomes bearing the genes into tissue culture cells.
The relaxation of imprinting of Igf2 in vivo will be studied to understand
how imprinting can be erased in somatic cells. The second specific aim
will focus on the function of the H19 gene, and its possible involvement
in the mechanism of imprinting. A series of mutations in the gene and its
transcriptional control regions will be generated through homologous
recombination in embryonic stem cells. The phenotype of mice that have
inherited either maternal and paternal null mutations will be determined.
The basis for the late fetal lethality caused by extra copies of H19 will
be studied by introducing both wild type and mutant copies of the gene
into embryonic stem cells, in order to establish lines of mice which
transmit extra copies of the gene. The nature of the proteins complexed in
the H19 particle will be determined by purifying the particle and cloning
the proteins contained within it. The third specific aim is to elucidate
the function of imprinting in eutherian mammals by identifying how it
evolved. The Igf2 and H19 genes will be identified and cloned from
marsupials and monotremes, and tested for allele-specific expression. The
likelihood that the H19 gene arose during mammalian speciation as a
duplication of XIST, a gene which maps to the X chromosome inacti...

## Key facts

- **NIH application ID:** 2190002
- **Project number:** 1R01GM051460-01
- **Recipient organization:** PRINCETON UNIVERSITY
- **SAM.gov UEI:** NJ1YPQXQG7U5
- **Principal Investigator:** SHIRLEY M. TILGHMAN
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 1994
- **Award amount:** $238,354
- **Award type:** 1
- **Project period:** 1994-08-01 → 1998-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/2190002

## Citation

> US National Institutes of Health, RePORTER application 2190002, H19--A MODEL FOR PARENTAL IMPRINTING IN THE MOUSE (1R01GM051460-01). Retrieved via MORVS 2026-10-25 from https://api.morvs.ai/grant/nih/2190002. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*