Cardiac pathologies in mouse loss of imprinting models are due to misexpression of H19 long noncoding RNA

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Abstract

Maternal loss of imprinting (LOI) at the H19/IGF2 locus results in biallelic IGF2 and reduced H19 expression and is associated with Beckwith-Wiedemann syndrome (BWS). We use mouse models for LOI to understand the relative importance of Igf2 and H19 mis-expression in BWS phenotypes. Here we focus on cardiovascular phenotypes and show that neonatal cardiomegaly is exclusively dependent on increased Igf2. Circulating IGF2 binds cardiomyocyte receptors to hyperactivate mTOR signaling, resulting in cellular hyperplasia and hypertrophy. These Igf2-dependent phenotypes are transient: cardiac size returns to normal once Igf2 expression is suppressed postnatally. However, reduced H19 expression is sufficient to cause progressive heart pathologies including fibrosis and reduced ventricular function. In the heart, H19 expression is primarily in endothelial cells (ECs) and regulates EC differentiation both, in vivo and in vitro. Finally, we establish novel mouse models to show that cardiac phenotypes depend on H19 lncRNA interactions with Mirlet7 microRNAs.

Data availability

Sequencing data are deposited in the NCBI Gene Expression Omnibus (GEO) under series accession number GSE111418.

The following data sets were generated

1. Mitra A
2. Park K
3. Yu Z
4. Springer D
5. Rahat B
6. Pfeifer K
(2020) Mis-expression of Igf2 and H19 work independently on distinct cell types to cause cardiomyopathy in a Beckwtih Wiedemann mouse model
NCBI Gene Expression Omnibus, GSE111418.

http://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE111418

Article and author information

Author details

Ki-Sun Park

Developmental Biology, Eunice Kennedy Shriver National Institute of Child Health and Human Development of the National Institutes of Health, Bethesda, United States

Competing interests
The authors declare that no competing interests exist.
Beenish Rahat

Developmental Biology, Eunice Kennedy Shriver National Institute of Child Health and Human Development of the National Institutes of Health, Bethesda, United States

Competing interests
The authors declare that no competing interests exist.
Hyung Chul Lee

Developmental Biology, Eunice Kennedy Shriver National Institute of Child Health and Human Development of the National Institutes of Health, Bethesda, United States

Competing interests
The authors declare that no competing interests exist.
Zu-Xi Yu

The Pathology Core, National Heart, Lung, and Blood Institute, Bethesda, United States

Competing interests
The authors declare that no competing interests exist.
Jacob Noeker

Developmental Biology, Eunice Kennedy Shriver National Institute of Child Health and Human Development of the National Institutes of Health, Bethesda, United States

Competing interests
The authors declare that no competing interests exist.

"This ORCID iD identifies the author of this article:" 0000-0002-4344-3114
Apratim Mitra

The Eunice Kennedy Shriver National Institutes of Child Health and Human Development, NIH, Bethesda, United States

Competing interests
The authors declare that no competing interests exist.
Connor M Kean

Developmental Biology, Eunice Kennedy Shriver National Institute of Child Health and Human Development of the National Institutes of Health, Bethesda, United States

Competing interests
The authors declare that no competing interests exist.
Russell H Knutsen

Laboratory of Vascular and Matrix Genetics, National Heart Lung and Blood Institute of the National Institutes of Health, Bethesda, United States

Competing interests
The authors declare that no competing interests exist.
Danielle Springer

National Heart Lung and Blood Institute, National Heart Lung and Blood Institute of the National Institutes of Health, Bethesda, United States

Competing interests
The authors declare that no competing interests exist.
Claudia M Gebert

Developmental Biology, Eunice Kennedy Shriver National Institute of Child Health and Human Development of the National Institutes of Health, Bethesda, United States

Competing interests
The authors declare that no competing interests exist.
Beth A Kozel

Laboratory of Vascular and Matrix Genetics, National Heart Lung and Blood Institute of the National Institutes of Health, Bethesda, United States

Competing interests
The authors declare that no competing interests exist.
Karl Pfeifer

Developmental Biology, Eunice Kennedy Shriver National Institute of Child Health and Human Development of the National Institutes of Health, Bethesda, United States

For correspondence
pfeiferk@mail.nih.gov

Competing interests
The authors declare that no competing interests exist.

"This ORCID iD identifies the author of this article:" 0000-0002-0254-682X

Funding

Eunice Kennedy Shriver National Institute of Child Health and Human Development Division of Intramural Research (ZIAHD001804)

Karl Pfeifer

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Ethics

Animal experimentation: This study was performed in strict accordance with the recommendations in the Guide for the Care and Use of Laboratory Animals of the National Institutes of Health. All animals were handled according to approved institutional animal care and use committee (IACUC) protocols (050 and 063) of the Eunice Kennedy Shriver National Institute of Child Health and Human Development. Surgery was performed under Avertin anesthesia and every effort was made to minimize suffering.

Copyright

This is an open-access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 public domain dedication.