The <i>H19</i> Imprinting Control Region Mediates Preimplantation Imprinted Methylation of Nearby Sequences in Yeast Artificial Chromosome Transgenic Mice

Okamura, Eiichi; Matsuzaki, Hitomi; Sakaguchi, Ryuuta; Takahashi, Takuri; Fukamizu, Akiyoshi; Tanimoto, Koichi

doi:10.1128/mcb.01003-12

Cited by 12 publications

(13 citation statements)

References 57 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…To demonstrate a role for postfertilization paternal allele-specific methylation activity at the endogenous locus, we narrowed its essential sequences in YAC-TgM (Figs 4 and 5) (Okamura et al, 2013b) and deleted them from the endogenous paternal H19 ICR. Although gametic methylation of the mutant, endogenous H19 ICR was not affected, its methylation level was diminished soon after fertilization (Fig.…”

Section: Discussionmentioning

confidence: 99%

“…We previously demonstrated that the 1.7-kb 'ICR21' fragment covering CTCF sites 1 and 2 (Fig. 4A) was sufficient to recapitulate paternal allele-specific DNA methylation after fertilization in YAC-TgM (Okamura et al, 2013b). We thus generated a series of 5′-truncated H19 ICR fragments: the ICR4321S fragment, in which the 5′-end of the 2.9-kb H19 ICR fragment (766 bp) was deleted but all four CTCF sites remained; and the ICR432 fragment, which is 173 bp shorter than the ICR4321S fragment and lacks CTCF site 1 (Fig.…”

Section: Germline Methylation Of the Endogenous H19 Icr Is Inhibited mentioning

confidence: 99%

See 1 more Smart Citation

De novoDNA methylation through 5'-segment of theH19ICR maintains its imprint during early embryogenesis

et al. 2015

Self Cite

View full text Add to dashboard Cite

Genomic imprinting is a major monoallelic gene expression regulatory mechanism in mammals, and depends on gametespecific DNA methylation of specialized cis-regulatory elements called imprinting control regions (ICRs). Allele-specific DNA methylation of the ICRs is faithfully maintained at the imprinted loci throughout development, even in early embryos where genomes undergo extensive epigenetic reprogramming, including DNA demethylation, to acquire totipotency. We previously found that an ectopically introduced H19 ICR fragment in transgenic mice acquired paternal allele-specific methylation in the somatic cells of offspring, whereas it was not methylated in sperm, suggesting that its gametic and postfertilization modifications were separable events. We hypothesized that this latter activity might contribute to maintenance of the methylation imprint in early embryos. Here, we demonstrate that methylation of the paternally inherited transgenic H19 ICR commences soon after fertilization in a maternal DNMT3A-and DNMT3L-dependent manner. When its germline methylation was partially obstructed by insertion of insulator sequences, the endogenous paternal H19 ICR also exhibited postfertilization methylation. Finally, we refined the responsible sequences for this activity in transgenic mice and found that deletion of the 5′ segment of the endogenous paternal H19 ICR decreased its methylation after fertilization and attenuated Igf2 gene expression. These results demonstrate that this segment of the H19 ICR is essential for its de novo postfertilization DNA methylation, and that this activity contributes to the maintenance of imprinted methylation at the endogenous H19 ICR during early embryogenesis.

show abstract

Section: Discussionmentioning

confidence: 99%

Section: Germline Methylation Of the Endogenous H19 Icr Is Inhibited mentioning

confidence: 99%

De novoDNA methylation through 5'-segment of theH19ICR maintains its imprint during early embryogenesis

et al. 2015

Self Cite

View full text Add to dashboard Cite

show abstract

“…(26)(27)(28)(29)(30), predominantly methylates hemimethylated CpG dinucleotides in the genome, and is considered to be the key maintenance methyltransferase during cell division (29)(30)(31)(32)(33). The DNMT2 gene is the most highly conserved of the methyltransferases in eukaryotes, and has been identified in organisms that exhibit DNA methylation, as well as in those that do not (26)(27)(28)(29)(30). DNMT3a and DNMT3b primarily perform de novo methyl transfer reactions via interactions with transcriptional repressors.…”

Section: Dna Methylationmentioning

confidence: 99%

DNA methylation in spermatogenesis and male infertility

Cui¹,

Xuan

Wu³

et al. 2016

Experimental and Therapeutic Medicine

View full text Add to dashboard Cite

Abstract. Infertility is a significant problem for human reproduction, with males and females equally affected. However, the molecular mechanisms underlying male infertility remain unclear. Spermatogenesis is a highly complex process involving mitotic cell division, meiosis cell division and spermiogenesis; during this period, unique and extensive chromatin and epigenetic modifications occur to bring about specific epigenetic profiles in spermatozoa. It has recently been suggested that the dysregulation of epigenetic modifications, in particular the methylation of sperm genomic DNA, may serve an important role in the development of numerous diseases. The present study is a comprehensive review on the topic of male infertility, aiming to elucidate the association between sperm genomic DNA methylation and poor semen quality in male infertility. In addition, the current status of the genetic and epigenetic determinants of spermatogenesis in humans is discussed. Contents1. Introduction 2. DNA methylation 3. DNA methylation and spermatogenesis 4. DNA methylation and genomic imprinting 5. DNA methylation and male infertility 6. Conclusion IntroductionEpigenetics is the study of genomic structural modifications that affect gene expression without altering the underlying nucleotide sequence (1-3). Epigenetic mechanisms involved in the regulation of gene expression include the regulation of non-coding RNA, chromatin remodeling, DNA methylation and histone modifications (4,5). Of these mechanisms, DNA methylation has been implicated in numerous biological functions, such as the development of spermatozoa and early embryos, and the repression of endogenous retrotransposons, while it also has a wide range of effects in gene expression (2,3,6). The dysregulation of DNA methylation has previously been associated with various human disorders, and has been shown to increase the risk of fertilization failure, dysfunction in embryogenesis, perinatal mortality, congenital abnormalities, preterm birth and low birth weight (7-11). The present review assesses the significance of DNA methylation in spermatogenesis in order to elucidate the association between the dysregulation of DNA methylation and male infertility. This may provide a basis for the prevention and treatment of male infertility, as well as permit the evaluation of the epigenetic quality of sperm in order to reduce the risk of epigenetic diseases in cases where conception is performed by assisted reproductive technology (ART). DNA methylationEpigenetic mechanisms are critical regulators of gene expression during spermatogenesis that may influence male fertility (12-14). Cytosine, a key DNA base, is methylated at the position, typically in the context of CpG dinucleotides. The methylation of constitutive heterochromatic and promoter regions is generally associated with reduced gene transcription (Fig. 1A) (15-18). Therefore, DNA methylation is a type of epigenetic modification that can effectively promote gene silencing (Fig. 1B). The methyl group for this chemical modif...

show abstract

“…DNA was purified with the QIAquick PCR purification kit (Qiagen, Venlo, The Netherlands) and subjected to qPCR analysis. The endogenous H19 ICR and Necdin sequences were analyzed as positive and negative controls, respectively [56]. LCR-HS5 and 3’HS1 primer sets are as follows: …”

Section: Methodsmentioning

confidence: 99%

No evidence for transvection in vivo by a superenhancer:promoter pair integrated into identical open chromatin at the Rosa26 locus

Tanimoto

Matsuzaki

Okamura

et al. 2018

Preprint

Self Cite

View full text Add to dashboard Cite

24Long-range associations between enhancers and their target gene promoters have been shown 25 to play critical roles in executing genome function. Recent variations of chromosome capture 26 technology have revealed a conprehensive view of intra-and inter-chromosomal contacts 27 between specific genomic sites. The locus control region of the β-globin genes (β-LCR) is a 28 super-enhancer that is capable of activating all of the β-like globin genes within the locus in cis 29 through physical interaction by forming DNA loops. CTCF helps to mediate loop formation 30 between LCR-HS5 and 3'HS1 in the human β-globin locus, in this way thought to contribute to 31 the formation of a "chromatin hub". The β-globin locus is also in close physical proximity to 32 other erythrocyte-specific genes located long distances away on the same chromosome. In 33 this case, erythrocyte-specific genes gather together at a shared "transcription factory" for 34 co-transcription. Theoretically, enhancers could also activate target gene promoters on 35 different chromosomes in trans, a phenomenon originally described as transvection in 36 Drosophilla. Although close physical proximity has been reported for the β-LCR and the 37 β-like globin genes when integrated at the mouse homologous loci in trans, their structural and 38 functional interactions were found to be rare, possibly because a lack of suitable regulatory 3 39 elements that might facilitate trans interactions. Therefore, we re-evaluated presumptive 40 transvection-like enhancer-promoter communication by introducing CTCF binding sites and 41 erythrocyte-specific transcription units into both LCR-enhancer and β-promoter alleles, each 42 inserted into the mouse ROSA26 locus on separate chromosomes. Following cross-mating of 43 mice to place the two mutant loci at the identical chromosomal position and into active 44 chromation in trans, their transcriptional output was evaluated. The results demonstrate that 45 there was no significant functional association between the LCR and the β-globin gene in trans 46 even in this idealized experimental context. 49Gene expression is tightly regulated by DNA cis elements and their binding trans-factors, in 50 which specific enhancer-promoter communications play a pivotal role. While genome-wide 51 sequencing of the human and mouse genomes disclosed the number of genes to be more than 52 20,000, the number of enhancer elements is predicted to far exceed the number of genes [1]. 53Because accumulating evidence suggests that perturbation of enhancer function can be a 54 major cause of pathogenesis in human diseases [2], it is of paramount importance to assign the 55 activity of any individual enhancer to a specific target gene(s) in order to predict its function. 56Recent genome-wide interactome analyses revealed that enhancers can physically interact with 57 genes over enormous distances, exceeding several hundreds of kilobase pairs in cis, or even 58 with genes located on different chromosomes in trans [3], suggesting the presence of molecular 59...

show abstract

The H19 Imprinting Control Region Mediates Preimplantation Imprinted Methylation of Nearby Sequences in Yeast Artificial Chromosome Transgenic Mice

Cited by 12 publications

References 57 publications

De novoDNA methylation through 5'-segment of theH19ICR maintains its imprint during early embryogenesis

De novoDNA methylation through 5'-segment of theH19ICR maintains its imprint during early embryogenesis

DNA methylation in spermatogenesis and male infertility

No evidence for transvection in vivo by a superenhancer:promoter pair integrated into identical open chromatin at the Rosa26 locus

Contact Info

Product

Resources

About