# Sequences controlling H19 Gene Imprinting

> **NIH NIH R01** · UNIVERSITY OF PENNSYLVANIA · 2024 · $415,833

## Abstract

Abstract
A few hundred genes in mammals are regulated by genomic imprinting. These genes are epigenetically
marked and exhibit parental-specific expression. Imprinting plays a role in the transmission of a number of
human disorders, including Beckwith-Wiedemann Syndrome (BWS), Silver-Russell Syndrome (SRS), Prader-
Willi Syndrome and Angelman Syndrome, in that the sex of the parent that transmits the affected gene(s)
determines whether offspring will be affected. Aberrant imprinted gene expression is also involved in the onset
or progression of cancers, such as Wilms tumors. The overall goal of our work is to elucidate the mechanism
by which parental identity of imprinted genes is established and maintained. The in-depth study of imprinted
genes can additionally inform our understanding of genome regulation and nuclear architecture as imprinted
genes are located in large domains and are often regulated by long non-coding RNAs, CTCF-dependent
insulators, and allele-specific epigenetic modifications. These studies will employ the H19/Igf2 and
Grb10/Ddc1a imprinted domains, both of which harbor CTCF-binding imprinting control regions (ICRs), which
regulate imprinting. In Specific Aim 1, we will investigate the role of the H19/Igf2 ICR in allelic DNA methylation
acquisition and the maintenance of imprinting. We will engineer mice with humanized ICRs and human iPSCs
that have common BWS deletions and study the mechanism by which these deletions contribute to DNA
methylation defects and loss of imprinting. Additionally, because mice inheriting the full-length humanized ICR
paternally fail to establish and maintain DNA methylation, we will assess the cause of this male germline-
specific DNA methylation failure, providing insight into how paternally-methylated ICRs are epigenetically
modified in the male germline. In Specific Aim 2, we will elucidate the mechanism of imprinting at the
Grb10/Ddc1a imprinted locus. These genes exhibit tissue-specific imprinting; Grb10 is expressed from the
maternal allele in somatic cells and switches to the paternal allele in neurons while the Ddc1a isoform is
expressed from the paternal allele in heart. To determine the role of CTCF in allele- and tissue-specific
expression, we will generate CTCF binding site deletions in the ICR in mice and examine the consequences of
these mutations on imprinting of Grb10 and Ddc1a. We have also identified a new tissue and allele-specific
CTCF-binding element that is developmentally regulated and critical to Grb10/Ddc1a imprinting, which we
propose to function as an insulator. We will investigate this newly described insulator through deletion of a
putative mesoderm-specific enhancer. Together, these experiments will enable a greater understanding of
imprinting as well as regulation of parental allelic modifications, chromatin and genome architecture.

## Key facts

- **NIH application ID:** 10865066
- **Project number:** 5R01GM051279-31
- **Recipient organization:** UNIVERSITY OF PENNSYLVANIA
- **Principal Investigator:** MARISA S. BARTOLOMEI
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $415,833
- **Award type:** 5
- **Project period:** 1994-08-01 → 2025-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10865066

## Citation

> US National Institutes of Health, RePORTER application 10865066, Sequences controlling H19 Gene Imprinting (5R01GM051279-31). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10865066. Licensed CC0.

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