Humanized H19/Igf2 locus reveals diverged imprinting mechanism between mouse and human and reflects Silver-Russell syndrome phenotypes.
Genomic imprinting affects a subset of genes in mammals, such that they are expressed in a monoallelic, parent-of-origin-specific manner. These genes are regulated by imprinting control regions (ICRs), cis-regulatory elements that exhibit allele-specific differential DNA methylation. Although genomic imprinting is conserved in mammals, ICRs are genetically divergent across species. This raises the fundamental question of whether the ICR plays a species-specific role in regulating imprinting at a given locus. We addressed this question at the H19/insulin-like growth factor 2 (Igf2) imprinted locus, the misregulation of which is associated with the human imprinting disorders Beckwith-Wiedemann syndrome (BWS) and Silver-Russell syndrome (SRS). We generated a knock-in mouse in which the endogenous H19/Igf2 ICR (mIC1) is replaced by the orthologous human ICR (hIC1) sequence, designated H19(hIC1) We show that hIC1 can functionally replace mIC1 on the maternal allele. In contrast, paternally transmitted hIC1 leads to growth restriction, abnormal hIC1 methylation, and loss of H19 and Igf2 imprinted expression. Imprint establishment at hIC1 is impaired in the male germ line, which is associated with an abnormal composition of histone posttranslational modifications compared with mIC1. Overall, this study reveals evolutionarily divergent paternal imprinting at IC1 between mice and humans. The conserved maternal imprinting mechanism and function at IC1 demonstrates the possibility of modeling maternal transmission of hIC1 mutations associated with BWS in mice. In addition, we propose that further analyses in the paternal knock-in H19(+/hIC1) mice will elucidate the molecular mechanisms that may underlie SRS.
Department of Cell and Developmental Biology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104;
Stella K
SK
Hur
Department of Environmental, Biological, and Pharmaceutical Sciences and Technologies, Second University of Naples, 81100 Caserta, Italy;
Andrea
A
Freschi
Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599;
Folami
F
Ideraabdullah
Department of Cell and Developmental Biology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104;
Joanne L
JL
Thorvaldsen
Department of Cell and Developmental Biology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104;
Lacey J
LJ
Luense
Department of Cell and Developmental Biology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104;
Angela H
AH
Weller
Department of Cell and Developmental Biology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104;
Shelley L
SL
Berger
Department of Environmental, Biological, and Pharmaceutical Sciences and Technologies, Second University of Naples, 81100 Caserta, Italy; flavia.cerrato@unina2.it andrea.riccio@igb.cnr.it bartolom@mail.med.upenn.edu.
Flavia
F
Cerrato
Department of Environmental, Biological, and Pharmaceutical Sciences and Technologies, Second University of Naples, 81100 Caserta, Italy; Institute of Genetics and Biophysics A. Buzzati-Traverso, 80131 Naples, Italy flavia.cerrato@unina2.it andrea.riccio@igb.cnr.it bartolom@mail.med.upenn.edu.
Andrea
A
Riccio
Department of Cell and Developmental Biology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104; flavia.cerrato@unina2.it andrea.riccio@igb.cnr.it bartolom@mail.med.upenn.edu.
Marisa S
MS
Bartolomei
D000483:Alleles; D000818:Animals; D019175:DNA Methylation / Q000235:genetics; D004622:Embryo, Mammalian / Q000378:metabolism; D005260:Female; D018390:Gene Targeting; D056426:Genetic Loci; D018392:Genomic Imprinting; D006657:Histones / Q000378:metabolism; D006801:Humans; D007335:Insulin-Like Growth Factor II / Q000235:genetics*; D008239:Lysine / Q000378:metabolism; D008297:Male; D008810:Mice, Inbred C57BL; D010641:Phenotype; D062085:RNA, Long Noncoding / Q000235:genetics*; D056730:Silver-Russell Syndrome / Q000235:genetics* / Q000473:pathology*; D013091:Spermatogenesis / Q000235:genetics; D013094:Spermatozoa / Q000378:metabolism
C094335:H19 long non-coding RNA; D006657:Histones; D062085:RNA, Long Noncoding; D007335:Insulin-Like Growth Factor II; D008239:Lysine
DNA methylation; H19; IGF2; Silver–Russell syndrome; genomic imprinting