Cardiac pathologies in mouse loss of imprinting models are due to misexpression of H19 long noncoding RNA
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...
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doaj-9585b4d7825b4eb19926c26cb2be1f3c2021-09-08T13:41:48ZengeLife Sciences Publications LtdeLife2050-084X2021-08-011010.7554/eLife.67250Cardiac pathologies in mouse loss of imprinting models are due to misexpression of H19 long noncoding RNAKi-Sun Park0https://orcid.org/0000-0003-1322-767XBeenish Rahat1https://orcid.org/0000-0003-0371-2356Hyung Chul Lee2Zu-Xi Yu3Jacob Noeker4https://orcid.org/0000-0002-4344-3114Apratim Mitra5Connor M Kean6Russell H Knutsen7https://orcid.org/0000-0001-6761-6502Danielle Springer8https://orcid.org/0000-0002-6261-9744Claudia M Gebert9https://orcid.org/0000-0002-1282-1602Beth A Kozel10https://orcid.org/0000-0002-9757-7118Karl Pfeifer11https://orcid.org/0000-0002-0254-682XDivision of Intramural Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, United StatesDivision of Intramural Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, United StatesDivision of Intramural Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, United StatesPathology Core, National Heart Lung and Blood Institute, National Institutes of Health, Bethesda, United StatesDivision of Intramural Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, United StatesDivision of Intramural Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, United StatesDivision of Intramural Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, United StatesLaboratory of Vascular and Matrix Genetics, National Heart Lung and Blood Institute, National Institutes of Health, Bethesda, United StatesMurine Phenotyping Core, National Heart Lung and Blood Institute, National Institutes of Health, Bethesda, United StatesDivision of Intramural Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, United StatesLaboratory of Vascular and Matrix Genetics, National Heart Lung and Blood Institute, National Institutes of Health, Bethesda, United StatesDivision of Intramural Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, United StatesMaternal 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.https://elifesciences.org/articles/67250genomic imprintingH19 lncRNAIGF2beckwith wiedemann syndromeepigeneticsheart |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Ki-Sun Park Beenish Rahat Hyung Chul Lee Zu-Xi Yu Jacob Noeker Apratim Mitra Connor M Kean Russell H Knutsen Danielle Springer Claudia M Gebert Beth A Kozel Karl Pfeifer |
spellingShingle |
Ki-Sun Park Beenish Rahat Hyung Chul Lee Zu-Xi Yu Jacob Noeker Apratim Mitra Connor M Kean Russell H Knutsen Danielle Springer Claudia M Gebert Beth A Kozel Karl Pfeifer Cardiac pathologies in mouse loss of imprinting models are due to misexpression of H19 long noncoding RNA eLife genomic imprinting H19 lncRNA IGF2 beckwith wiedemann syndrome epigenetics heart |
author_facet |
Ki-Sun Park Beenish Rahat Hyung Chul Lee Zu-Xi Yu Jacob Noeker Apratim Mitra Connor M Kean Russell H Knutsen Danielle Springer Claudia M Gebert Beth A Kozel Karl Pfeifer |
author_sort |
Ki-Sun Park |
title |
Cardiac pathologies in mouse loss of imprinting models are due to misexpression of H19 long noncoding RNA |
title_short |
Cardiac pathologies in mouse loss of imprinting models are due to misexpression of H19 long noncoding RNA |
title_full |
Cardiac pathologies in mouse loss of imprinting models are due to misexpression of H19 long noncoding RNA |
title_fullStr |
Cardiac pathologies in mouse loss of imprinting models are due to misexpression of H19 long noncoding RNA |
title_full_unstemmed |
Cardiac pathologies in mouse loss of imprinting models are due to misexpression of H19 long noncoding RNA |
title_sort |
cardiac pathologies in mouse loss of imprinting models are due to misexpression of h19 long noncoding rna |
publisher |
eLife Sciences Publications Ltd |
series |
eLife |
issn |
2050-084X |
publishDate |
2021-08-01 |
description |
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. |
topic |
genomic imprinting H19 lncRNA IGF2 beckwith wiedemann syndrome epigenetics heart |
url |
https://elifesciences.org/articles/67250 |
work_keys_str_mv |
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