Extensive tissue-specific variation of allelic methylation in the Igf2 gene during mouse fetal development: relation to expression and imprinting

Weber, Michaël; Milligan, Laura; Delalbre, Annie; Antoine, Etienne; Brunel, Claude; Cathala, Guy; Forné, Thierry

doi:10.1016/s0925-4773(00)00573-6

Cited by 53 publications

(47 citation statements)

References 40 publications

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“…After birth, both genes are strongly down-regulated in all tissues with the exception of skeletal muscle, in which H19 continues to be expressed (Weber et al, 2001).…”

Section: Expression Profi Lesmentioning

confidence: 99%

The <i>H19</i> gene: regulation and function of a non-coding RNA

Gabory

Ripoche

Yoshimizu

et al. 2006

Cytogenet Genome Res

205

149

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The H19 gene encodes a 2.3-kb non-coding mRNA which is strongly expressed during embryogenesis. This gene belongs to an imprinted cluster, conserved on mouse chromosome 7 and human chromosome 11p15. H19 is maternally expressed and the neighbouring Igf2 gene is transcribed from the paternal allele. These two genes are co-expressed in endoderm- and mesoderm-derived tissues during embryonic development, which suggests a common mechanism of regulation. The regulatory elements (imprinted con- trol region, CTCF insulation, different enhancer sequences, promoters of the two genes, matrix attachment regions) confer a differential chromatin architecture to the two parental alleles leading to reciprocal expression. The role of the H19 gene is unclear but different aspects have been proposed. H19 influences growth by way of a cis control on Igf2 expression. Although H19^–/– mice are viable, a role for this gene during development has been suggested by viable H19^–/– parthenogenetic mice. Finally it has been described as a putative tumour suppressor gene. H19 has been studied by numerous laboratories over the last fifteen years, nevertheless the function of this non-coding RNA remains to be elucidated.

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“…After birth, both genes are strongly down-regulated in all tissues with the exception of skeletal muscle, in which H19 continues to be expressed (Weber et al, 2001).…”

Section: Expression Profi Lesmentioning

confidence: 99%

The <i>H19</i> gene: regulation and function of a non-coding RNA

Gabory

Ripoche

Yoshimizu

et al. 2006

Cytogenet Genome Res

205

149

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“…Noteworthy, the neighboring DMR0 is known to be mostly unmethylated on the paternal allele in the placenta (23), whereas in liver, DMR2 is highly methylated on that allele (8,32). Thus, like MAR2 in liver, MAR0 attachment occurs on the paternal Igf2 allele, although the adjacent DMR shows the converse allelic methylation pattern.…”

Section: Vol 23 2003 Genomic Imprinting Controls Igf2 Mars 8955mentioning

confidence: 99%

“…Importantly, both MAR0 and MAR2 attachments are restricted to the paternal allele, while the neighboring DMRs display opposite allelic methylation patterns. In placenta, DMR0 is preferentially methylated on the maternal allele (23) while in liver, DMR2 is highly methylated on the paternal allele (8,32). Moreover, MAR2 becomes detached on the paternal allele in 30-day-old mouse liver, while DMR2 remains highly methylated (32), and, therefore, DNA methylation on its own is clearly not sufficient to explain nuclear matrix attachment.…”

mentioning

confidence: 98%

Genomic Imprinting Controls Matrix Attachment Regionsin the Igf2Gene

Weber

Hagège

Murrell

et al. 2003

Molecular and Cellular Biology

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Genomic imprinting at the Igf2/H19 locus originates from allele-specific DNA methylation, which modifies the affinity of some proteins for their target sequences. Here, we show that AT-rich DNA sequences located in the vicinity of previously characterized differentially methylated regions (DMRs) of the imprinted Igf2 gene are conserved between mouse and human. These sequences have all the characteristics of matrix attachment regions (MARs), which are known as versatile regulatory elements involved in chromatin structure and gene expression. Combining allele-specific nuclear matrix binding assays and real-time PCR quantification, we show that retention of two of these Igf2 MARs (MAR0 and MAR2) in the nuclear matrix fraction depends on the tissue and is specific to the paternal allele. Furthermore, on this allele, the Igf2 MAR2 is functionally linked to the neighboring DMR2 while, on the maternal allele, it is controlled by the imprinting-control region. Our work clearly demonstrates that genomic imprinting controls matrix attachment regions in the Igf2 gene.On the distal part of mouse chromosome 7, the Igf2 and H19 genes are separated by 72 kbp. At this locus, imprinting originates from paternal germ line-specific methylation that impairs the binding of a protein factor (CTCF) to the intergenic imprinting-control region (ICR). On the maternal allele, binding of CTCF results in activation of an insulator, which prevents Igf2 expression by blocking promoter access to a set of enhancers located downstream of H19 (2, 14). Thus, Igf2 gene expression is restricted to the paternal allele, whereas H19 is maternally expressed. However, Igf2 imprinting also involves additional differentially methylated regions (DMR0, DMR1, and DMR2) that control regional epigenetic modifications in a hierarchical and tissue-specific fashion (19). DMR1, located upstream of the fetal Igf2 promoters, is preferentially methylated on the paternal allele and acts as a methylation-sensitive silencer in several mesodermal tissues (5). DMR2 maps to exons 5 to 6 and augments transcription on the methylated paternal allele (24). Finally, DMR0 is maternally methylated in the placenta and overlaps the placenta-specific P0 promoter (23). All these DMRs display tissue-specific methylation patterns, and we have recently proposed that their methylation profiles are regionally coordinated through long-range chromatin interactions (19).Here, we identify intragenic AT-rich DNA sequences in the Igf2 gene that are contiguous to previously identified DMRs. These sequences have all the characteristics of matrix attachment regions (MARs) and are conserved in humans. MARs are operationally defined in MAR assays by their ability to associate to a nuclear matrix or scaffold (17) and have been implicated in the regulation of chromatin structure and gene expression. They are frequently associated with enhancers (4, 10, 11) and promote chromatin accessibility and histone acetylation (7,9,15,20,26). MARs may also sometimes act as boundaries, preventing the spreading of p...

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“…For both Igf2 and Lnpp5f_v3 it was shown that methylation of their associated DMRs was different between alleles and between tissues. 20,21 As the Imprinting Control Regions (ICR) of these genes are not located in the DMR showing the combined allele-and tissue-specific methylation, we hypothesize that the DMR we identified in this study is not the ICR of STOX1, but that the parental origin of the primary imprinting mark is reflected in the methylation status of the DMR in intron 1 of STOX1.…”

Section: Dmr In Intron 1 Of Stox1mentioning

confidence: 75%