Sex-specific exons control DNA methyltransferase in mammalian germ cells

Development ◽  
1998 ◽  
Vol 125 (5) ◽  
pp. 889-897 ◽  
Author(s):  
C. Mertineit ◽  
J.A. Yoder ◽  
T. Taketo ◽  
D.W. Laird ◽  
J.M. Trasler ◽  
...  
Keyword(s):  
Germ Cells ◽  
Dna Methyltransferase ◽  
De Novo ◽  
Male Meiosis ◽  
Specific Expression ◽  
Oocyte Growth ◽  
Methyl Transferase ◽  
Developmental Potential ◽  
Allele Specific ◽  
Methylation Patterns

The spermatozoon and oocyte genomes bear sex-specific methylation patterns that are established during gametogenesis and are required for the allele-specific expression of imprinted genes in somatic tissues. The mRNA for Dnmt1, the predominant maintenance and de novo DNA (cytosine-5)-methyl transferase in mammals, is present at high levels in postmitotic murine germ cells but undergoes alternative splicing of sex-specific 5′ exons, which controls the production and localization of enzyme during specific stages of gametogenesis. An oocyte-specific 5′ exon is associated with the production of very large amounts of active Dnmt1 protein, which is truncated at the N terminus and sequestered in the cytoplasm during the later stages of oocyte growth, while a spermatocyte-specific 5′ exon interferes with translation and prevents production of Dnmt1 during the prolonged crossing-over stage of male meiosis. During the course of postnatal oogenesis, Dnmt1 is present at high levels in nuclei only in growing dictyate oocytes, a stage during which gynogenetic developmental potential is lost and biparental developmental potential is gained.

scholarly journals Structural insights into CpG-specific DNA methylation by human DNA methyltransferase 3B

2020 ◽  
Vol 48 (7) ◽  
pp. 3949-3961 ◽  
Author(s):  
Chien-Chu Lin ◽  
Yi-Ping Chen ◽  
Wei-Zen Yang ◽  
James C K Shen ◽  
Hanna S Yuan
Keyword(s):  
Dna Methylation ◽  
Dna Methyltransferase ◽  
Cytosine Methylation ◽  
Catalytic Domain ◽  
De Novo ◽  
Water Channel ◽  
Dna Methyltransferases ◽  
Structural Basis ◽  
Cpg Sites ◽  
Methylation Patterns

Abstract DNA methyltransferases are primary enzymes for cytosine methylation at CpG sites of epigenetic gene regulation in mammals. De novo methyltransferases DNMT3A and DNMT3B create DNA methylation patterns during development, but how they differentially implement genomic DNA methylation patterns is poorly understood. Here, we report crystal structures of the catalytic domain of human DNMT3B–3L complex, noncovalently bound with and without DNA of different sequences. Human DNMT3B uses two flexible loops to enclose DNA and employs its catalytic loop to flip out the cytosine base. As opposed to DNMT3A, DNMT3B specifically recognizes DNA with CpGpG sites via residues Asn779 and Lys777 in its more stable and well-ordered target recognition domain loop to facilitate processive methylation of tandemly repeated CpG sites. We also identify a proton wire water channel for the final deprotonation step, revealing the complete working mechanism for cytosine methylation by DNMT3B and providing the structural basis for DNMT3B mutation-induced hypomethylation in immunodeficiency, centromere instability and facial anomalies syndrome.

scholarly journals Persistent epigenetic memory impedes rescue of the telomeric phenotype in human ICF iPSCs following DNMT3B correction

eLife ◽  
2019 ◽  
Vol 8 ◽  
Author(s):  
Shir Toubiana ◽  
Miriam Gagliardi ◽  
Mariarosaria Papa ◽  
Roberta Manco ◽  
Maty Tzukerman ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Dna Methyltransferase ◽  
De Novo ◽  
Pharmacological Intervention ◽  
Icf Syndrome ◽  
Genome Wide ◽  
Mammalian Genomes ◽  
Induced Pluripotent ◽  
Methylation Patterns

DNA methyltransferase 3B (DNMT3B) is the major DNMT that methylates mammalian genomes during early development. Mutations in human DNMT3B disrupt genome-wide DNA methylation patterns and result in ICF syndrome type 1 (ICF1). To study whether normal DNA methylation patterns may be restored in ICF1 cells, we corrected DNMT3B mutations in induced pluripotent stem cells from ICF1 patients. Focusing on repetitive regions, we show that in contrast to pericentromeric repeats, which reacquire normal methylation, the majority of subtelomeres acquire only partial DNA methylation and, accordingly, the ICF1 telomeric phenotype persists. Subtelomeres resistant to de novo methylation were characterized by abnormally high H3K4 trimethylation (H3K4me3), and short-term reduction of H3K4me3 by pharmacological intervention partially restored subtelomeric DNA methylation. These findings demonstrate that the abnormal epigenetic landscape established in ICF1 cells restricts the recruitment of DNMT3B, and suggest that rescue of epigenetic diseases with genome-wide disruptions will demand further manipulation beyond mutation correction.

scholarly journals Transcriptional overlap links DNA hypomethylation with DNA hypermethylation at adjacent promoters in cancer

2021 ◽  
Author(s):  
Jean S Fain ◽  
Axelle Loriot ◽  
Anna Diacofotaki ◽  
Aurelie Van Tongelen ◽  
Charles De Smet
Keyword(s):  
Dna Methylation ◽  
Dna Methyltransferase ◽  
De Novo ◽  
Tumor Development ◽  
Epigenetic Mark ◽  
Dna Hypomethylation ◽  
Dna Hypermethylation ◽  
Bioinformatics Analyses ◽  
Genomic Regions ◽  
Methylation Patterns

DNA methylation is an epigenetic mark associated with gene repression. It is now well established that tumor development involves alterations in DNA methylation patterns, which include both gains (hypermethylation) and losses (hypomethylation) of methylation marks in different genomic regions. The mechanisms underlying these two opposite, yet co-existing, alterations in tumors remain unclear. While studying the human MAGEA6/GABRA3 gene locus, we observed that DNA hypomethylation in tumor cells can lead to the activation of a long transcript (CT-GABRA3) that overlaps downstream promoters (GABRQ and GABRA3) and triggers their hypermethylation. Overlapped promoters displayed increases in H3K36me3, a histone mark known to be deposited during progression of the transcription machinery and to stimulate de novo DNA methylation. Consistent with such a processive mechanism, increases in H3K36me3 and DNA methylation were observed over the entire region covered by the CT-GABRA3 overlapping transcript. Importantly, experimental induction of CT-GABRA3 by depletion of DNMT1 DNA methyltransferase, resulted in a similar pattern of increased DNA methylation in the MAGEA6/GABRA3 locus. Bioinformatics analyses in lung cancer datasets identified other genomic loci displaying this process of coupled DNA hypo- and hypermethylation. In several of these loci, DNA hypermethylation affected tumor suppressor genes, e.g. RERG and PTPRO. Together, our work reveals that focal DNA hypomethylation in tumors can indirectly contribute to hypermethylation of nearby promoters through activation of overlapping transcription, and establishes therefore an unsuspected connection between these two opposite epigenetic alterations.

scholarly journals Lineage and Parent-of-Origin Effects in DNA Methylation of Honey Bees (Apis mellifera) Revealed by Reciprocal Crosses and Whole-Genome Bisulfite Sequencing

2020 ◽  
Vol 12 (8) ◽  
pp. 1482-1492
Author(s):  
Xin Wu ◽  
David A Galbraith ◽  
Paramita Chatterjee ◽  
Hyeonsoo Jeong ◽  
Christina M Grozinger ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Honey Bees ◽  
Specific Expression ◽  
Africanized Honey Bee ◽  
Allele Specific ◽  
Parent Of Origin ◽  
Origin Effects ◽  
Genetic Background Effects ◽  
Allele Specific Methylation ◽  
Methylation Patterns

Abstract Parent-of-origin methylation arises when the methylation patterns of a particular allele are dependent on the parent it was inherited from. Previous work in honey bees has shown evidence of parent-of-origin-specific expression, yet the mechanisms regulating such pattern remain unknown in honey bees. In mammals and plants, DNA methylation is known to regulate parent-of-origin effects such as genomic imprinting. Here, we utilize genotyping of reciprocal European and Africanized honey bee crosses to study genome-wide allele-specific methylation patterns in sterile and reproductive individuals. Our data confirm the presence of allele-specific methylation in honey bees in lineage-specific contexts but also importantly, though to a lesser degree, parent-of-origin contexts. We show that the majority of allele-specific methylation occurs due to lineage rather than parent-of-origin factors, regardless of the reproductive state. Interestingly, genes affected by allele-specific DNA methylation often exhibit both lineage and parent-of-origin effects, indicating that they are particularly labile in terms of DNA methylation patterns. Additionally, we re-analyzed our previous study on parent-of-origin-specific expression in honey bees and found little association with parent-of-origin-specific methylation. These results indicate strong genetic background effects on allelic DNA methylation and suggest that although parent-of-origin effects are manifested in both DNA methylation and gene expression, they are not directly associated with each other.

scholarly journals Transcriptional overlap links DNA hypomethylation with DNA hypermethylation at adjacent promoters in cancer

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Jean S. Fain ◽  
Axelle Loriot ◽  
Anna Diacofotaki ◽  
Aurélie Van Tongelen ◽  
Charles De Smet
Keyword(s):  
Dna Methylation ◽  
Dna Methyltransferase ◽  
De Novo ◽  
Tumor Development ◽  
Transcriptional Elongation ◽  
Dna Hypomethylation ◽  
Dna Hypermethylation ◽  
Bioinformatics Analyses ◽  
Genomic Regions ◽  
Methylation Patterns

AbstractTumor development involves alterations in DNA methylation patterns, which include both gains (hypermethylation) and losses (hypomethylation) in different genomic regions. The mechanisms underlying these two opposite, yet co-existing, alterations in tumors remain unclear. While studying the human MAGEA6/GABRA3 gene locus, we observed that DNA hypomethylation in tumor cells can lead to the activation of a long transcript (CT-GABRA3) that overlaps downstream promoters (GABRQ and GABRA3) and triggers their hypermethylation. Overlapped promoters displayed increases in H3K36me3, a histone mark deposited during transcriptional elongation and known to stimulate de novo DNA methylation. Consistent with such a processive mechanism, increases in H3K36me3 and DNA methylation were observed over the entire region covered by the CT-GABRA3 overlapping transcript. Importantly, experimental induction of CT-GABRA3 by depletion of DNMT1 DNA methyltransferase, resulted in a similar pattern of regional DNA hypermethylation. Bioinformatics analyses in lung cancer datasets identified other genomic loci displaying this process of coupled DNA hypo/hypermethylation, and some of these included tumor suppressor genes, e.g. RERG and PTPRO. Together, our work reveals that focal DNA hypomethylation in tumors can indirectly contribute to hypermethylation of nearby promoters through activation of overlapping transcription, and establishes therefore an unsuspected connection between these two opposite epigenetic alterations.

scholarly journals Modeling allele-specific expression at the gene and SNP levels simultaneously by a Bayesian logistic mixed regression model

2019 ◽  
Vol 20 (1) ◽  
Author(s):  
Jing Xie ◽  
Tieming Ji ◽  
Marco A. R. Ferreira ◽  
Yahan Li ◽  
Bhaumik N. Patel ◽  
...  
Keyword(s):  
High Throughput ◽  
High Throughput Sequencing ◽  
Mixed Model ◽  
Linear Mixed Model ◽  
De Novo ◽  
Bovine Genome ◽  
Whole Genome Analysis ◽  
Specific Expression ◽  
Allele Specific Expression ◽  
Allele Specific

Abstract Background High-throughput sequencing experiments, which can determine allele origins, have been used to assess genome-wide allele-specific expression. Despite the amount of data generated from high-throughput experiments, statistical methods are often too simplistic to understand the complexity of gene expression. Specifically, existing methods do not test allele-specific expression (ASE) of a gene as a whole and variation in ASE within a gene across exons separately and simultaneously. Results We propose a generalized linear mixed model to close these gaps, incorporating variations due to genes, single nucleotide polymorphisms (SNPs), and biological replicates. To improve reliability of statistical inferences, we assign priors on each effect in the model so that information is shared across genes in the entire genome. We utilize Bayesian model selection to test the hypothesis of ASE for each gene and variations across SNPs within a gene. We apply our method to four tissue types in a bovine study to de novo detect ASE genes in the bovine genome, and uncover intriguing predictions of regulatory ASEs across gene exons and across tissue types. We compared our method to competing approaches through simulation studies that mimicked the real datasets. The R package, BLMRM, that implements our proposed algorithm, is publicly available for download at https://github.com/JingXieMIZZOU/BLMRM. Conclusions We will show that the proposed method exhibits improved control of the false discovery rate and improved power over existing methods when SNP variation and biological variation are present. Besides, our method also maintains low computational requirements that allows for whole genome analysis.

scholarly journals Haplotype-resolved genomes of geminivirus-resistant and geminivirus-susceptible African cassava cultivars

BMC Biology ◽  
2019 ◽  
Vol 17 (1) ◽  
Author(s):  
Joel-E. Kuon ◽  
Weihong Qi ◽  
Pascal Schläpfer ◽  
Matthias Hirsch-Hoffmann ◽  
Philipp Rogalla von Bieberstein ◽  
...  
Keyword(s):  
De Novo ◽  
Haplotype Diversity ◽  
Mosaic Disease ◽  
Cassava Mosaic Disease ◽  
Specific Expression ◽  
Tropical Regions ◽  
Genome Maps ◽  
Gene Sets ◽  
Allele Specific ◽  
Genome Assemblies

Abstract Background Cassava is an important food crop in tropical and sub-tropical regions worldwide. In Africa, cassava production is widely affected by cassava mosaic disease (CMD), which is caused by the African cassava mosaic geminivirus that is transmitted by whiteflies. Cassava breeders often use a single locus, CMD2, for introducing CMD resistance into susceptible cultivars. The CMD2 locus has been genetically mapped to a 10-Mbp region, but its organization and genes as well as their functions are unknown. Results We report haplotype-resolved de novo assemblies and annotations of the genomes for the African cassava cultivar TME (tropical Manihot esculenta), which is the origin of CMD2, and the CMD-susceptible cultivar 60444. The assemblies provide phased haplotype information for over 80% of the genomes. Haplotype comparison identified novel features previously hidden in collapsed and fragmented cassava genomes, including thousands of allelic variants, inter-haplotype diversity in coding regions, and patterns of diversification through allele-specific expression. Reconstruction of the CMD2 locus revealed a highly complex region with nearly identical gene sets but limited microsynteny between the two cultivars. Conclusions The genome maps of the CMD2 locus in both 60444 and TME3, together with the newly annotated genes, will help the identification of the causal genetic basis of CMD2 resistance to geminiviruses. Our de novo cassava genome assemblies will also facilitate genetic mapping approaches to narrow the large CMD2 region to a few candidate genes for better informed strategies to develop robust geminivirus resistance in susceptible cassava cultivars.

scholarly journals Integrative genomic analysis unifying epigenetic inheritance in adaptation and canalization

2019 ◽  
Author(s):  
Abhay Sharma
Keyword(s):  
De Novo ◽  
Genomic Analysis ◽  
Epigenetic Inheritance ◽  
Recent Analysis ◽  
Evolutionary Significance ◽  
Evolutionary Adaptation ◽  
Specific Expression ◽  
Gene Sets ◽  
Specific Finding ◽  
Allele Specific

AbstractEpigenetic inheritance, especially its biomedical and evolutionary significance, is an immensely interesting but highly controversial subject. Notably, a recent analysis of existing multi-omics has supported the mechanistic plausibility of epigenetic inheritance and its implications in disease and evolution. The evolutionary support stemmed from the specific finding that genes associated with cold induced inheritance and with latitudinal adaptation in mice are exceptionally common. Here, a similar gene set overlap analysis is presented that integrates cold induced inheritance with evolutionary adaptation and genetic canalization in cold environment in Drosophila. Genes showing differential expression in inheritance specifically overrepresent gene sets associated with differential and allele specific expression, though not with genome-wide genetic differentiation, in adaptation. On the other hand, the differentiated outliers uniquely overrepresent genes dysregulated by radicicol, a decanalization inducer. Both gene sets in turn exclusively show enrichment of genes that accumulate, in intended experimental lines, de novo mutations, a potential source of canalization. Successively, the three gene sets distinctively overrepresent genes exhibiting, between mutation accumulation lines, invariable expression, a potential signal for canalization. Sequentially, the four gene sets solely display enrichment of genes grouped in gene ontology under transcription factor activity, a signature of regulatory canalization. Cumulatively, the analysis suggests that epigenetic inheritance possibly contributes to evolutionary adaptation in the form of cis regulatory variations, with trans variations arising in the course of genetic canalization.

scholarly journals The conserved DNMT1 dependent methylation regions in human cells are vulnerable to environmental rotenone

2019 ◽  
Author(s):  
Dana M. Freeman ◽  
Dan Lou ◽  
Yanqiang Li ◽  
Suzanne N. Martos ◽  
Zhibin Wang
Keyword(s):  
Human Genome ◽  
Dna Methyltransferase ◽  
Neuronal Development ◽  
Imprinted Genes ◽  
Dependent Manner ◽  
Binding Motifs ◽  
Expression Of Genes ◽  
Human Genomes ◽  
Allele Specific ◽  
Methylation Patterns

AbstractAllele-specific DNA methylation (ASM) describes genomic loci that maintain CpG methylation at only one inherited allele rather than having coordinated methylation across both alleles. The most prominent of these regions are germline ASMs (gASMs) that control the expression of imprinted genes in a parent of origin-dependent manner and are associated with disease. However, our recent report reveals numerous ASMs at non-imprinted genes. These non-germline ASMs are dependent on DNA methyltransferase 1 (DNMT1) and strikingly show the feature of random, switchable monoallelic methylation patterns in the mouse genome. The significance of these ASMs to human health has not been explored. Due to their shared allelicity with gASMs, herein, we propose that non-traditional ASMs are sensitive to exposures in association with human disease. We first explore their conservancy in the human genome. Our data show that our putative non-germline ASMs were in conserved regions of the human genome and located adjacent to genes vital for neuronal development and maturation. We next tested the hypothesized vulnerability of these regions by exposing human embryonic kidney cell HEK293 with the neurotoxicant rotenone for 24h. Indeed,14 genes adjacent to our identified regions were differentially expressed from RNA-sequencing. We analyzed the base-resolution methylation patterns of the predicted non-germline ASMs at two neurological genes, HCN2 and NEFM, with potential to increase the risk of neurodegeneration. Both regions were significantly hypomethylated in response to rotenone. Our data indicate that non-germline ASMs seem conserved between mouse and human genomes, overlap important regulatory factor binding motifs, and regulate the expression of genes vital to neuronal function. These results support the notion that ASMs are sensitive to environmental factors and may alter the risk of neurological disease later in life by disrupting neuronal development.

scholarly journals Genome and Transcriptome Sequencing of Populus × sibirica Identified Sex-Associated Allele-Specific Expression of the CLC Gene

2021 ◽  
Vol 12 ◽  
Author(s):  
Elena N. Pushkova ◽  
George S. Krasnov ◽  
Valentina A. Lakunina ◽  
Roman O. Novakovskiy ◽  
Liubov V. Povkhova ◽  
...  
Keyword(s):  
Transcriptome Sequencing ◽  
Dna Methyltransferase ◽  
Sequencing Data ◽  
Specific Expression ◽  
Allelic Variants ◽  
Allele Specific Expression ◽  
T Complex ◽  
Populus Suaveolens ◽  
Complex Protein ◽  
Allele Specific

Transcriptome sequencing of leaves, catkin axes, and flowers from male and female trees of Populus × sibirica and genome sequencing of the same plants were performed for the first time. The availability of both genome and transcriptome sequencing data enabled the identification of allele-specific expression. Such an analysis was performed for genes from the sex-determining region (SDR). P. × sibirica is an intersectional hybrid between species from sections Aigeiros (Populus nigra) and Tacamahaca (Populus laurifolia, Populus suaveolens, or Populus × moskoviensis); therefore, a significant number of heterozygous polymorphisms were identified in the SDR that allowed us to distinguish between alleles. In the SDR, both allelic variants of the TCP (T-complex protein 1 subunit gamma), CLC (Chloride channel protein CLC-c), and MET1 (DNA-methyltransferase 1) genes were expressed in females, while in males, two allelic variants were expressed for TCP and MET1 but only one allelic variant prevailed for CLC. Targeted sequencing of TCP, CLC, and MET1 regions on a representative set of trees confirmed the sex-associated allele-specific expression of the CLC gene in generative and vegetative tissues of P. × sibirica. Our study brings new knowledge on sex-associated differences in Populus species.

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