Interaction between differentially methylated regions partitions the imprinted genes Igf2 and H19 into parent-specific chromatin loops
Abstract
Imprinted genes are expressed from only one of the parental alleles and are marked epigenetically by DNA methylation and histone modifications. The paternally expressed gene insulin-like growth-factor 2 (Igf2) is separated by approximately 100 kb from the maternally expressed noncoding gene H19 on mouse distal chromosome 7. Differentially methylated regions in Igf2 and H19 contain chromatin boundaries, silencers and activators and regulate the reciprocal expression of the two genes in a methylation-sensitive manner by allowing them exclusive access to a shared set of enhancers. Various chromatin models have been proposed that separate Igf2 and H19 into active and silent domains. Here we used a GAL4 knock-in approach as well as the chromosome conformation capture technique to show that the differentially methylated regions in the imprinted genes Igf2 and H19 interact in mice. These interactions are epigenetically regulated and partition maternal and paternal chromatin into distinct loops. This generates a simple epigenetic switch for Igf2 through which it moves between an active and a silent chromatin domain.
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An insulated neighborhood on the maternal allele allows an enhancer-promoter interaction that activates the H19 gene but not the IGF2 gene, which is excluded from the neighborhood.
“An insulated neighborhood on the maternal allele allows an enhancer-promoter interaction that activates the H19 gene but not the IGF2 gene, which is excluded from the neighborhood.”
From Insulated Neighborhoods: Structural and Functional Units of Mammalian Gene Control (2016) · cites this paper as Murrell et al., 2004
Parent-of-origin specific gene activity at the imprinted IGF2/H19 locus is controlled by allele-specific CTCF-CTCF interactions that constrain enhancer-gene contacts in a DNA methylation-dependent manner.
“Parent-of-origin specific gene activity at the imprinted IGF2/H19 locus is controlled by allele-specific CTCF-CTCF interactions that constrain enhancer-gene contacts in a DNA methylation-dependent manner (Figure 6A) (Kurukuti et al., 2006; Murrell et al., 2004).”
From Insulated Neighborhoods: Structural and Functional Units of Mammalian Gene Control (2016) · cites this paper as Murrell et al., 2004
A larger insulated neighborhood is formed on the paternal allele to allow an enhancer-promoter interaction that activates the IGF2 gene.
“A larger insulated neighborhood is formed on the paternal allele to allow an enhancer-promoter interaction that activates the IGF2 gene.”
From Insulated Neighborhoods: Structural and Functional Units of Mammalian Gene Control (2016) · cites this paper as Murrell et al., 2004
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“At the imprinted H19-Igf2 locus differentially methylated regions (DMR) control parent of origin-specific gene expression such that H19 and Igf2 are only expressed from the maternal and paternal alleles, respectively.”
BackgroundInfluentialCTCF: the protein, the binding partners, the binding sites and their chromatin loops
Holwerda, S. J. B., & de Laat, W. L. (2013) · Philosophical Transactions of the Royal Society B Biological Sciences · doi:10.1098/rstb.2012.0369 · Cited by 230 · see citing works
Hogart, A., Nagarajan, R. P., Patzel, K. A., Yasui, D. H., & LaSalle, J. M. (2007) · Human Molecular Genetics · doi:10.1093/hmg/ddm014 · Cited by 234 · see citing works
Jelinic, P., & Shaw, P. H. (2006) · The Journal of Pathology · doi:10.1002/path.2116 · Cited by 231 · see citing works
Genomic Imprinting in Mammals: Emerging Themes and Established Theories
Wood, A. J., & Oakey, R. J. (2006) · PLoS Genetics · doi:10.1371/journal.pgen.0020147 · Cited by 230 · see citing works
Nishikawa, K., Iwamoto, Y., Kobayashi, Y., Katsuoka, F., Kawaguchi, S.-I., Tsujita, T., Nakamura, T., Kato, S., Yamamoto, M. P., Takayanagi, H., et al. (2015) · Nature Medicine · doi:10.1038/nm.3774 · Cited by 229 · see citing works
Enhancer and promoter interactions—long distance calls
Krivega, I., & Dean, A. (2012) · Current Opinion in Genetics & Development · doi:10.1016/j.gde.2011.11.001 · Cited by 225 · see citing works
“In any case, the enhancer– gene loop appears to be necessary for transcriptional upregulation as gain or loss of a competing promoter [22,23], reduction of loop-associated proteins [15–18] or interruption of looping by an insulator [24,25] all affect transcriptional outcome.”
BackgroundAn Overview of Genome Organization and How We Got There: from FISH to Hi-C
Fraser, J., Williamson, I., Bickmore, W. A., & Dostie, J. (2015) · Microbiology and Molecular Biology Reviews · doi:10.1128/mmbr.00006-15 · Cited by 218 · see citing works
The H19 gene: regulation and function of a non-coding RNA
Gabory, A., Ripoche, M., Yoshimizu, T., & Dandolo, L. (2006) · Cytogenetic and Genome Research · doi:10.1159/000090831 · Cited by 227 · see citing works
“A model of chromatin loops has also been proposed, leading to distribution of the genes in active and inactive nuclear compartments (Banerjee and Smallwood, 1995; Murrell et al., 2004; Kato and Sasaki, 2005).”
BackgroundReplication and transcription: Shaping the landscape of the genome
Chakalova, L., Debrand, E., Mitchell, J. A., Osborne, C. S., & Fraser, P. (2005) · Nature Reviews Genetics · doi:10.1038/nrg1673 · Cited by 218 · see citing works
“Loop structures have also been detected in imprinte”
BackgroundGenomics tools for unraveling chromosome architecture
van Steensel, B., & Dekker, J. (2010) · Nature Biotechnology · doi:10.1038/nbt.1680 · Cited by 216 · see citing works
Chromatin Insulators: Linking Genome Organization to Cellular Function
Phillips‐Cremins, J. E., & Corces, V. G. (2013) · Molecular Cell · doi:10.1016/j.molcel.2013.04.018 · Cited by 213 · see citing works
“…2 (Igf2), and major histocompatibility complex class II genomic loci indicated that CTCF sites are important for longrange interactions between specific genomic elements (Kurukuti et al., 2006; Li et al., 2008; Majumder et al., 2008; Murrell et al., 2004; Splinter et al., 2006; Yoon et al., 2007).”
BackgroundJing, H., Vakoc, C. R., Ying, L., Mandat, S. A., Wang, H., Zheng, X., & Blobel, G. A. (2008) · Molecular Cell · doi:10.1016/j.molcel.2007.11.020 · Cited by 213 · see citing works
“Distinct chromatin configurations between active and inactive alleles have been observed at the imprinted Igf2 and H19 genes (Kurukuti et al., 2006; Murrell et al., 2004; Yoon et al., 2007).”
BackgroundWuerffel, R., Wang, L., Grigera, F., Manis, J. P., Selsing, E., Perlot, T., Alt, F. W., Cogné, M., Pinaud, E., & Kenter, A. L. (2007) · Immunity · doi:10.1016/j.immuni.2007.09.007 · Cited by 208 · see citing works
“Loop structures have also been detected in imprinted (Horike et al., 2005; Murrell et al., 2004) and cytokine (Spilianakis and Flavell, 2004) clusters and between chromatin boundary elements (Blanton et al., 2003).”
Chromatin Insulators: Regulatory Mechanisms and Epigenetic Inheritance
Bushey, A. M., Dorman, E. R., & Corces, V. G. (2008) · Molecular Cell · doi:10.1016/j.molcel.2008.08.017 · Cited by 210 · see citing works
“Additionally, an endogenous example of functional loop formation has been found at the H19 imprinting control region (ICR) in mice, which binds CTCF in an allele-specific manner (Kurukuti et al., 2006; Murrell et al., 2004; Yoon et al., 2007).”
BackgroundPcG Proteins, DNA Methylation, and Gene Repression by Chromatin Looping
Tiwari, V. K., McGarvey, K. M., Licchesi, J. D. F., Ohm, J. E., Herman, J. G., Schübeler, D., & Baylin, S. B. (2008) · PLoS Biology · doi:10.1371/journal.pbio.0060306 · Cited by 205 · see citing works
CTCF-dependent enhancer-blocking by alternative chromatin loop formation
Hou, C., Zhao, H., Tanimoto, K., & Dean, A. (2008) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0808506106 · Cited by 205 · see citing works
Jelinic, P., Stehle, J., & Shaw, P. H. (2006) · PLoS Biology · doi:10.1371/journal.pbio.0040355 · Cited by 206 · see citing works
“ChIP was performed according to the Upstate Biotechnology's protocol (Upstate Biotechnology, Waltham, Massachusetts, United States) with minor changes. Adult mouse testes and embryonic gonads were homogenized in 5 ml and 1 ml of phosphate-buffered saline (PBS), respectively, and fixed with formaldehyde (1% v/v) for 10…”
MethodInfluentialConservation of the H19 noncoding RNA and H19-IGF2 imprinting mechanism in therians
Smits, G., Mungall, A. J. J., Griffiths‐Jones, S., Smith, P., Beury, D., Matthews, L. H., Rogers, J., Pask, A. J., Shaw, G., VandeBerg, J. L., et al. (2008) · Nature Genetics · doi:10.1038/ng.168 · Cited by 197 · see citing works
“In mouse neonatal liver, this insulator shields the Igf2 gene from enhancers by a looping mechanis”
BackgroundLewis, A., & Reik, W. (2006) · Cytogenetic and Genome Research · doi:10.1159/000090818 · Cited by 198 · see citing works
“Indeed, the unknown protein(s) involved in interactions between the methylated DMRs in the paternal specifi c chromatin loop in the Igf2/H19 locus (Murrell et al., 2004) is probably an MBD.”
BackgroundLi, T., Hu, J., Qiu, X., Ling, J., Chen, H., Wang, S., Hou, A., Vu, T. H., & Hoffman, A. R. (2008) · Molecular and Cellular Biology · doi:10.1128/mcb.00204-08 · Cited by 197 · see citing works
“First, it orchestrates long-distance communication via an intrachromosomal loop between the Igf2 promoters and the H19 ICR (Fig. 1) (42, 21 ).”
BackgroundMethodInfluentialArchitectural roles of multiple chromatin insulators at the human apolipoprotein gene cluster
Mishiro, T., Ishihara, K., Hino, S., Tsutsumi, S., Aburatani, H., Shirahige, K., Kinoshita, Y., & Nakao, M. (2009) · The EMBO Journal · doi:10.1038/emboj.2009.81 · Cited by 197 · see citing works
Hong, J. A., Kang, Y., Abdullaev, Z., Flanagan, P. T., Pack, S., Fischette, M. R., Adnani, M. T., Loukinov, D. I., Vatolin, S., Risinger, J. I., et al. (2005) · Cancer Research · doi:10.1158/0008-5472.can-05-0823 · Cited by 192 · see citing works
“Furthermore, the data do not exclude the possibility that alterations in chromatin structure within extended ‘‘looped’’ regions of the X chromosome which contain interacting CTCFbinding sites, as recently suggested for the IGF2/H19 (13, 50) and XIST (2) loci, as well as for several gene clusters that escape X chromoso…”
BackgroundInfluentialNon‐coding RNAs in imprinted gene clusters
Royo, H., & Cavaillé, J. (2008) · Biology of the Cell · doi:10.1042/bc20070126 · Cited by 191 · see citing works
“Imprinted long ncRNAs as simple miRNA precursors H19 ncRNA is part of a particularly well-studied imprinted gene cluster: the Igf2–H19 locus (for further discussion, see Murrell et al., 2004) (Figure 3).”
BackgroundBushey, A. M., Ramos, E., & Corces, V. G. (2009) · Genes & Development · doi:10.1101/gad.1798209 · Cited by 188 · see citing works
“More specifically, CTCFdependent loop formation that is necessary for allelespecific transcription has been observed within the mouse b-globin locus and at the imprinting control region (ICR) in the H19/Igf2 locus (Murrell et al. 2004; Kurukuti et al. 2006; Splinter et al. 2006; Yoon et al. 2007).”
BackgroundMapping networks of physical interactions between genomic elements using 5C technology
Dostie, J., & Dekker, J. (2007) · Nature Protocols · doi:10.1038/nprot.2007.116 · Cited by 184 · see citing works
Murrell, A., Rakyan, V. K., & Beck, S. (2005) · Human Molecular Genetics · doi:10.1093/hmg/ddi110 · Cited by 183 · see citing works
CTCF Genomic Binding Sites in Drosophila and the Organisation of the Bithorax Complex
Holohan, E. E., Kwong, C., Adryan, B., Bartkuhn, M., Herold, M. V. B., Renkawitz, R., Russell, S. R. H., & White, R. A. (2007) · PLoS Genetics · doi:10.1371/journal.pgen.0030112 · Cited by 176 · see citing works
Li, T., Vu, T. H., Ulaner, G. A., Littman, E. D., Ling, J., Chen, H., Hu, J., Behr, B. R., Giudice, L. C., & Hoffman, A. R. (2005) · Molecular Human Reproduction · doi:10.1093/molehr/gah230 · Cited by 176 · see citing works
“Murrell et al. (2004) have proposed a new model of Igf2-H19 imprinting whereby an epigenetic switch (consisting of the ICR ± CTCF and other unidentified protein complexes) turn on or turn off Igf2 gene expression by interacting with the Igf2 DMR2 or DMR1, respectively.”
BackgroundMethodInfluentialEvolution of Genomic Imprinting: Insights from Marsupials and Monotremes
Renfree, M. B., Hore, T. A., Shaw, G., Graves, J. A. M., & Pask, A. J. (2009) · Annual Review of Genomics and Human Genetics · doi:10.1146/annurev-genom-082908-150026 · Cited by 178 · see citing works
Kernohan, K. D., Jiang, Y. Y., Tremblay, D. C., Bonvissuto, A. C., Eubanks, J. H., Mann, M. R. W., & Bérubé, N. G. (2010) · Developmental Cell · doi:10.1016/j.devcel.2009.12.017 · Cited by 175 · see citing works
Epigenetic regulation of the Igf2/H19 gene cluster
Nordin, M., Bergman, D., Halje, M., Engström, W., & Ward, A. (2014) · Cell Proliferation · doi:10.1111/cpr.12106 · Cited by 170 · see citing works
Hübner, M. R., & Spector, D. L. (2010) · Annual Review of Biophysics · doi:10.1146/annurev.biophys.093008.131348 · Cited by 171 · see citing works
Genetics and Epigenetics of the Multifunctional Protein CTCF
Filippova, G. N. (2007) · Current topics in developmental biology/Current Topics in Developmental Biology · doi:10.1016/s0070-2153(07)80009-3 · Cited by 170 · see citing works
Valenzuela, L., & Kamakaka, R. T. (2006) · Annual Review of Genetics · doi:10.1146/annurev.genet.39.073003.113546 · Cited by 168 · see citing works
“These elements interact with one another to organize the domain into loops that are distinct for the maternal and paternal chromosomes (89, 121).”
BackgroundOn a chromosome far, far away: LCRs and gene expression
Dean, A. (2005) · Trends in Genetics · doi:10.1016/j.tig.2005.11.001 · Cited by 165 · see citing works
The transcriptional interactome: gene expression in 3D
Schoenfelder, S., Clay, I., & Fraser, P. (2010) · Current Opinion in Genetics & Development · doi:10.1016/j.gde.2010.02.002 · Cited by 158 · see citing works
Silencing by imprinted noncoding RNAs: is transcription the answer?
Pauler, F. M., Koerner, M. V., & Barlow, D. P. (2007) · Trends in Genetics · doi:10.1016/j.tig.2007.03.018 · Cited by 156 · see citing works
“A looping model that separates promoters from enhancers has also been proposed for the imprinted Igf2 cluster (Figure 1a) [59].”
BackgroundSun, J., Li, W., Sun, Y., Yu, D., Wen, X., Wang, H., Cui, J., Wang, G., Hoffman, A. R., & Hu, J. (2014) · Nucleic Acids Research · doi:10.1093/nar/gku549 · Cited by 156 · see citing works
A Novel H19 Antisense RNA Overexpressed in Breast Cancer Contributes to Paternal IGF2 Expression
Berteaux, N., Aptel, N., Cathala, G., Genton, C., Coll, J., Daccache, A., Spruyt, N., Hondermarck, H., Dugimont, T., Curgy, J., et al. (2008) · Molecular and Cellular Biology · doi:10.1128/mcb.02103-07 · Cited by 156 · see citing works
Cohesin regulates tissue-specific expression by stabilizing highly occupied cis -regulatory modulesPreprint
Faure, A. J., Schmidt, D., Watt, S., Schwalie, P. C., Wilson, M. D., Xu, H., Ramsay, R. G., Odom, D. T., & Flicek, P. (2012) · Genome Research · doi:10.1101/gr.136507.111 · Cited by 149 · see citing works
“…(3C) experiments in the wellcharacterized H19/Igf2 imprinting control region (ICR) indicate that CTCF regulates allele-specific expression of the H19 and Igf2 genes by controlling intrachromosomal looping interactions (Murrell et al. 2004; Kurukuti et al. 2006; Yoon et al. 2007; Engel et al. 2008).”
BackgroundThe role of long non-coding RNAs in genome formatting and expression
Angrand, P., Vennin, C., Bourhis, X. L., & Adriaenssens, É. (2015) · Frontiers in Genetics · doi:10.3389/fgene.2015.00165 · Cited by 151 · see citing works
“The H19/IGF2 locus contains other differentially methylated regions (DMRs), with DMR1 being a methylation-sensitive silencer and DMR2 being a methylation-sensitive activator (Constancia et al., 2000; Murrell et al., 2004).”
BackgroundFetal Alcohol Spectrum Disorders: The Epigenetic Perspective1
Haycock, P. (2009) · Biology of Reproduction · doi:10.1095/biolreprod.108.074690 · Cited by 149 · see citing works
Marinić, M., Aktaş, T., Ruf, S., & Spitz, F. (2013) · Developmental Cell · doi:10.1016/j.devcel.2013.01.025 · Cited by 142 · see citing works
Engel, N., Thorvaldsen, J. L., & Bartolomei, M. S. (2006) · Human Molecular Genetics · doi:10.1093/hmg/ddl237 · Cited by 148 · see citing works
“This interaction could involve direct physical interactions and looping out of chromatin, thereby partitioning the region into either active or inactive domains, as suggested by chromosome conformation capture (3C) studies at this locus ( 42 ).”
BackgroundMonk, D., Sanches, R. H. D. S., Arnaúd, P., Apostolidou, S., Hills, F. A., Abu-Amero, S. N., Murrell, A., Friess, H., Reik, W., Stanier, P., et al. (2006) · Human Molecular Genetics · doi:10.1093/hmg/ddl041 · Cited by 144 · see citing works
“Research into the imprinting control of this domain has revealed a complicated regulatory mechanism that utilizes multiple enhancers, boundary elements, histone modifications and complex physical DNA looping, which are all allele-specific and some of which are species-specific (7,8).”
BackgroundSmith, E. M., Lajoie, B. R., Jain, G., & Dekker, J. (2016) · The American Journal of Human Genetics · doi:10.1016/j.ajhg.2015.12.002 · Cited by 142 · see citing works
The three-dimensional architecture of Hox cluster silencing
Ferraiuolo, M. A., Rousseau, M., Miyamoto, C. M., Shenker, S., Wang, X. Q. D., Nadler, M. B., Blanchette, M., & Dostie, J. (2010) · Nucleic Acids Research · doi:10.1093/nar/gkq644 · Cited by 142 · see citing works
- Authors
- Murrell, A., Heeson, S., & Reik, W.
- Affiliations
- Babraham Institute (GB)
- Corresponding author
- Murrell, Adele
- Reik, Wolf
- Venue
- Nature Genetics
- Published
- 2004-07-25
- Volume
- 36
- Issue
- 8
- Pages
- 889-893
- ISSN
- 1061-4036 (ISSN-L)
- 1546-1718
- OpenAlex
- W2085509761
- Cited by
- 556
- References
- 30
- Citations by year
- 2026: 7 · 2025: 4 · 2024: 13 · 2023: 5 · 2022: 8 · 2021: 8 · 2020: 10 · 2019: 13 · 2018: 16 · 2017: 15 · 2016: 18 · 2015: 26 · 2014: 27 · 2013: 30 · 2012: 50
- FWCI
- 22.42
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature Genetics (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Syndromes and Imprinting
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Epigenetics and DNA Methylation
- Keywords
- genomic imprinting, insulin-like growth factor II, H19, differentially methylated regions, chromatin looping, DNA methylation, epigenetic regulation, chromosome conformation, epigenetic switch, mouse chromosome 7, gene silencing
- MeSH terms
- Animals, Chromatin, Insulin-Like Growth Factor II, Mice, Transgenic, Molecular Sequence Data, Genomic Imprinting, DNA Methylation, RNA, Untranslated, Mice, RNA, Long Noncoding
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