scholarly journals Divergent DNA methylation signatures of X chromosome regulation in marsupials and eutherians

2020 ◽  
Author(s):  
Devika Singh ◽  
Dan Sun ◽  
Andrew G. King ◽  
David E. Alquezar-Planas ◽  
Rebecca N. Johnson ◽  
...  
Keyword(s):  
Dna Methylation ◽  
X Chromosome ◽  
Specific Expression ◽  
X Chromosomes ◽  
Phascolarctos Cinereus ◽  
Male And Female ◽  
Inactive X Chromosome ◽  
Genome Wide ◽  
Promoter Dna Methylation ◽  
Promoter Dna

AbstractX chromosome inactivation (XCI) mediated by differential DNA methylation between sexes is well characterized in eutherian mammals. Although XCI is shared between eutherians and marsupials, the role of DNA methylation in marsupial XCI remains contested. Here we examine genome-wide signatures of DNA methylation from methylation maps across fives tissues from a male and female koala (Phascolarctos cinereus) and present the first whole genome, multi-tissue marsupial “methylome atlas.” Using these novel data, we elucidate divergent versus common features of marsupial and eutherian DNA methylation. First, tissue-specific differential DNA methylation in marsupials primarily occurs in gene bodies. Second, females show significant global reduction (hypomethylation) of X chromosome DNA methylation compared to males. We show that this pattern is also observed in eutherians. Third, on average, promoter DNA methylation shows little difference between male and female koala X chromosomes, a pattern distinct from that of eutherians. Fourth, the sex-specific DNA methylation landscape upstream of Rsx, the primary lncRNA associated with marsupial XCI, is consistent with the epigenetic regulation of female-(and presumably inactive X chromosome-) specific expression. Finally, we utilize the prominent female X chromosome hypomethylation and classify 98 previously unplaced scaffolds as X-linked, contributing an additional 14.6 Mb (21.5 %) to genomic data annotated as the koala X chromosome. Our work demonstrates evolutionarily divergent pathways leading to functionally conserved patterns of XCI in two deep branches of mammals.

scholarly journals Koala methylomes reveal divergent and conserved DNA methylation signatures of X chromosome regulation

2021 ◽  
Vol 288 (1945) ◽  
pp. 20202244
Author(s):  
Devika Singh ◽  
Dan Sun ◽  
Andrew G. King ◽  
David E. Alquezar-Planas ◽  
Rebecca N. Johnson ◽  
...  
Keyword(s):  
Dna Methylation ◽  
X Chromosome ◽  
Epigenetic Regulation ◽  
Specific Expression ◽  
X Chromosomes ◽  
Phascolarctos Cinereus ◽  
Male And Female ◽  
Inactive X Chromosome ◽  
Promoter Dna ◽  
Female Specific

X chromosome inactivation (XCI) mediated by differential DNA methylation between sexes is an iconic example of epigenetic regulation. Although XCI is shared between eutherians and marsupials, the role of DNA methylation in marsupial XCI remains contested. Here, we examine genome-wide signatures of DNA methylation across fives tissues from a male and female koala ( Phascolarctos cinereus ), and present the first whole-genome, multi-tissue marsupial ‘methylome atlas’. Using these novel data, we elucidate divergent versus common features of representative marsupial and eutherian DNA methylation. First, tissue-specific differential DNA methylation in koalas primarily occurs in gene bodies. Second, females show significant global reduction (hypomethylation) of X chromosome DNA methylation compared to males. We show that this pattern is also observed in eutherians. Third, on average, promoter DNA methylation shows little difference between male and female koala X chromosomes, a pattern distinct from that of eutherians. Fourth, the sex-specific DNA methylation landscape upstream of Rsx , the primary lnc RNA associated with marsupial XCI, is consistent with the epigenetic regulation of female-specific (and presumably inactive X chromosome-specific) expression. Finally, we use the prominent female X chromosome hypomethylation and classify 98 previously unplaced scaffolds as X-linked, contributing an additional 14.6 Mb (21.5%) to genomic data annotated as the koala X chromosome. Our work demonstrates evolutionarily divergent pathways leading to functionally conserved patterns of XCI in two deep branches of mammals.

scholarly journals Genome-wide Mapping Reveals Conservation of Promoter DNA Methylation Following Chicken Domestication

2015 ◽  
Vol 5 (1) ◽  
Author(s):  
Qinghe Li ◽  
Yuanyuan Wang ◽  
Xiaoxiang Hu ◽  
Yaofeng Zhao ◽  
Ning Li
Keyword(s):  
Dna Methylation ◽  
Genome Wide ◽  
Promoter Dna Methylation ◽  
Promoter Dna

scholarly journals High-resolution methylation analysis of the human hypoxanthine phosphoribosyltransferase gene 5' region on the active and inactive X chromosomes: correlation with binding sites for transcription factors.

1994 ◽  
Vol 14 (2) ◽  
pp. 1419-1430 ◽  
Author(s):  
I K Hornstra ◽  
T P Yang
Keyword(s):  
Dna Methylation ◽  
X Chromosome ◽  
Cpg Island ◽  
Hypoxanthine Phosphoribosyltransferase ◽  
Hprt Gene ◽  
Methylation Analysis ◽  
Kinase Gene ◽  
X Chromosomes ◽  
Cpg Dinucleotides ◽  
Inactive X Chromosome

DNA methylation within GC-rich promoters of constitutively expressed X-linked genes is correlated with transcriptional silencing on the inactive X chromosome in female mammals. For most X-linked genes, X chromosome inactivation results in transcriptionally active and inactive alleles occupying each female nucleus. To examine mechanisms responsible for maintaining this unique system of differential gene expression, we have analyzed the methylation of individual cytosine residues in the 5' CpG island of the human hypoxanthine phosphoribosyltransferase (HPRT) gene on the active and inactive X chromosomes. Methylation analysis of 142 CpG dinucleotides by genomic sequencing was carried out on purified DNA using the cytosine-specific Maxam and Gilbert DNA sequencing reaction in conjunction with ligation-mediated PCR. These studies demonstrate the 5' CpG islands of active and 5-azacytidine-reactivated alleles are essentially unmethylated while the inactive allele is hypermethylated. The inactive allele is completely methylated at nearly all CpG dinucleotides except in a 68-bp region containing four adjacent GC boxes where most CpG dinucleotides are either unmethylated or partially methylated. Curiously, these GC boxes exhibit in vivo footprints only on the active X chromosome, not on the inactive X. The methylation pattern of the inactive HPRT gene is strikingly different from that reported for the inactive X-linked human phosphoglycerate kinase gene which exhibits methylation at all CpG sites in the 5' CpG island. These results suggest that the position of methylated CpG dinucleotides, the density of methylated CpGs, the length of methylated regions, and/or chromatin structure associated with methylated DNA may have a role in repressing the activity of housekeeping promoters on the inactive X chromosome. The pattern of DNA methylation on the inactive human HPRT gene may also provide insight into the process of inactivating the gene early in female embryogenesis.

scholarly journals Molecular signatures of X chromosome inactivation and associations with clinical outcomes in epithelial ovarian cancer

2018 ◽  
Vol 28 (8) ◽  
pp. 1331-1342 ◽  
Author(s):  
Stacey J Winham ◽  
Nicholas B Larson ◽  
Sebastian M Armasu ◽  
Zachary C Fogarty ◽  
Melissa C Larson ◽  
...  
Keyword(s):  
Gene Expression ◽  
Ovarian Cancer ◽  
Dna Methylation ◽  
X Chromosome ◽  
Strong Association ◽  
X Chromosome Inactivation ◽  
Chromosome Inactivation ◽  
Specific Expression ◽  
Cluster Membership ◽  
Promoter Dna

AbstractX chromosome inactivation (XCI) is a key epigenetic gene expression regulatory process, which may play a role in women’s cancer. In particular tissues, some genes are known to escape XCI, yet patterns of XCI in ovarian cancer (OC) and their clinical associations are largely unknown. To examine XCI in OC, we integrated germline genotype with tumor copy number, gene expression and DNA methylation information from 99 OC patients. Approximately 10% of genes showed different XCI status (either escaping or being subject to XCI) compared with the studies of other tissues. Many of these genes are known oncogenes or tumor suppressors (e.g. DDX3X, TRAPPC2 and TCEANC). We also observed strong association between cis promoter DNA methylation and allele-specific expression imbalance (P = 2.0 × 10−10). Cluster analyses of the integrated data identified two molecular subgroups of OC patients representing those with regulated (N = 47) and dysregulated (N = 52) XCI. This XCI cluster membership was associated with expression of X inactive specific transcript (P = 0.002), a known driver of XCI, as well as age, grade, stage, tumor histology and extent of rl disease following surgical debulking. Patients with dysregulated XCI (N = 52) had shorter time to recurrence (HR = 2.34, P = 0.001) and overall survival time (HR = 1.87, P = 0.02) than those with regulated XCI, although results were attenuated after covariate adjustment. Similar findings were observed when restricted to high-grade serous tumors. We found evidence of a unique OC XCI profile, suggesting that XCI may play an important role in OC biology. Additional studies to examine somatic changes with paired tumor-normal tissue are needed.

scholarly journals Prenatal stress-induced programming of genome-wide promoter DNA methylation in 5-HTT-deficient mice

2014 ◽  
Vol 4 (10) ◽  
pp. e473-e473 ◽  
Author(s):  
K G Schraut ◽  
S B Jakob ◽  
M T Weidner ◽  
A G Schmitt ◽  
C J Scholz ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Prenatal Stress ◽  
Genome Wide ◽  
Promoter Dna Methylation ◽  
Promoter Dna ◽  
Deficient Mice

scholarly journals Frequent lack of repressive capacity of promoter DNA methylation identified through genome-wide epigenomic manipulation

2017 ◽  
Author(s):  
Ethan Ford ◽  
Matthew R. Grimmer ◽  
Sabine Stolzenburg ◽  
Ozren Bogdanovic ◽  
Alex de Mendoza ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Fusion Protein ◽  
Rna Polymerase Ii ◽  
Zinc Finger ◽  
Gene Promoters ◽  
Natural Conditions ◽  
Promoter Regions ◽  
Genome Wide ◽  
Promoter Dna Methylation ◽  
Promoter Dna

AbstractIt is widely assumed that the addition of DNA methylation at CpG rich gene promoters silences gene transcription. However, this conclusion is largely drawn from the observation that promoter DNA methylation inversely correlates with gene expression in natural conditions. The effect of induced DNA methylation on endogenous promoters has yet to be comprehensively assessed. Here, we induced the simultaneous methylation of thousands of promoters in the genome of human cells using an engineered zinc finger-DNMT3A fusion protein, enabling assessment of the effect of forced DNA methylation upon transcription, histone modifications, and DNA methylation persistence after the removal of the fusion protein. We find that DNA methylation is frequently insufficient to transcriptionally repress promoters. Furthermore, DNA methylation deposited at promoter regions associated with H3K4me3 is rapidly erased after removal of the zinc finger-DNMT3A fusion protein. Finally, we demonstrate that induced DNA methylation can exist simultaneously on promoter nucleosomes that possess the active histone modification H3K4me3, or DNA bound by the initiated form of RNA polymerase II. These findings suggest that promoter DNA methylation is not generally sufficient for transcriptional inactivation, with implications for the emerging field of epigenome engineering.One Sentence SummaryGenome-wide epigenomic manipulation of thousands of human promoters reveals that induced promoter DNA methylation is unstable and frequently does not function as a primary instructive biochemical signal for gene silencing and chromatin reconfiguration.

scholarly journals High-resolution methylation analysis of the human hypoxanthine phosphoribosyltransferase gene 5' region on the active and inactive X chromosomes: correlation with binding sites for transcription factors

1994 ◽  
Vol 14 (2) ◽  
pp. 1419-1430
Author(s):  
I K Hornstra ◽  
T P Yang
Keyword(s):  
Dna Methylation ◽  
X Chromosome ◽  
Cpg Island ◽  
Hypoxanthine Phosphoribosyltransferase ◽  
Hprt Gene ◽  
Methylation Analysis ◽  
Kinase Gene ◽  
X Chromosomes ◽  
Cpg Dinucleotides ◽  
Inactive X Chromosome

DNA methylation within GC-rich promoters of constitutively expressed X-linked genes is correlated with transcriptional silencing on the inactive X chromosome in female mammals. For most X-linked genes, X chromosome inactivation results in transcriptionally active and inactive alleles occupying each female nucleus. To examine mechanisms responsible for maintaining this unique system of differential gene expression, we have analyzed the methylation of individual cytosine residues in the 5' CpG island of the human hypoxanthine phosphoribosyltransferase (HPRT) gene on the active and inactive X chromosomes. Methylation analysis of 142 CpG dinucleotides by genomic sequencing was carried out on purified DNA using the cytosine-specific Maxam and Gilbert DNA sequencing reaction in conjunction with ligation-mediated PCR. These studies demonstrate the 5' CpG islands of active and 5-azacytidine-reactivated alleles are essentially unmethylated while the inactive allele is hypermethylated. The inactive allele is completely methylated at nearly all CpG dinucleotides except in a 68-bp region containing four adjacent GC boxes where most CpG dinucleotides are either unmethylated or partially methylated. Curiously, these GC boxes exhibit in vivo footprints only on the active X chromosome, not on the inactive X. The methylation pattern of the inactive HPRT gene is strikingly different from that reported for the inactive X-linked human phosphoglycerate kinase gene which exhibits methylation at all CpG sites in the 5' CpG island. These results suggest that the position of methylated CpG dinucleotides, the density of methylated CpGs, the length of methylated regions, and/or chromatin structure associated with methylated DNA may have a role in repressing the activity of housekeeping promoters on the inactive X chromosome. The pattern of DNA methylation on the inactive human HPRT gene may also provide insight into the process of inactivating the gene early in female embryogenesis.

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