Identification of distinct loci for de novo DNA methylation by DNMT3A and DNMT3B during mammalian development

Yagi, Masahide; Kabata, Mio; Tanaka, Akito; Ukai, Tomoyo; Ohta, Sho; Nakabayashi, Kazuhiko; Shimizu, Masahito; Hata, Kenichiro; Meissner, Alexander; Yamamoto, Takuya; Yamada, Yoshihiko

doi:10.1038/s41467-020-16989-w

Cited by 54 publications

(54 citation statements)

References 50 publications

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“…STK11 inhibits IL-1β release in macrophages [ 30 ]. Hypomethylation of STK11 gene body likely suppressed STK11 expression [ 56 , 57 ], which in turn increased IL-1β levels and magnified gouty inflammation ( Table 2 , Figure 5 ) [ 30 , 56 , 57 ]. NLRP12 also upregulated IL-1β in macrophages [ 31 ] and hypermethylation of NLRP12 gene body probably increased NLRP12 expression [ 56 , 57 ] and IL-1β release, thereby promoting gouty inflammation ( Table 2 , Figure 5 ) [ 31 , 56 , 57 ].…”

Section: Discussionmentioning

confidence: 99%

Cell lineage-specific methylome and genome alterations in gout

Tseng

Liao

Wong

et al. 2021

Aging

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In this study, we examined data from 69 gout patients and 1,455 non-gout controls using a MethylationEPIC BeadChip assay and Illumina HiSeq platform to identify lineage-specific epigenetic alterations and associated genetic factors that contributed to gouty inflammation. Cell lineage-specific differentially methylated sites were identified using CellDMC after adjusting for sex, age, alcohol drinking, smoking status, and smoking history (total pack-years). Different cell lineages displayed distinct differential methylation. Ingenuity Pathway Analysis and NetworkAnalyst indicated that many differential methylated sites were associated with interleukin-1β expression in monocytes. On the UCSC Genome Browser and WashU Epigenome Browser, metabolic trait, cis-methylation quantitative trait loci, genetic, and functional annotation analyses identified nine methylation loci located in interleukin-1β-regulating genes ( PRKCZ, CIDEC, VDAC1, CPT1A, BIRC2, BRCA1, STK11, and NLRP12 ) that were associated specifically with gouty inflammation. All nine sites mapped to active regulatory elements in monocytes. MoLoTool and ReMap analyses indicated that the nine methylation loci overlapped with binding sites of several transcription factors that regulated interleukin-1β production and gouty inflammation. Decreases in PRKCZ and STK11 methylation were also associated with higher numbers of first-degree relatives who also had gout. The gouty-inflammation specific methylome and genome alterations could potentially aid in the identification of novel therapeutic targets.

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Section: Discussionmentioning

confidence: 99%

Cell lineage-specific methylome and genome alterations in gout

Tseng

Liao

Wong

et al. 2021

Aging

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“…An important point to understand how DNAme is established and by which factors, is to also answer the question of “when” the considered factors begin to be expressed during development. As illustrated by the distinct DNAme profiles in TBRS and ICF1 patients, and in light of genome-wide methylome studies performed in Dnmt3 knock-out mouse models [ 5 , 73 , 92 , 93 ], the shaping of DNA methylomes by DNMT3 enzymes appears to rely on multiple factors including the timing of expression of DNMTs during development [ 94 ], their respective interactions with transcription factors [ 9 ] as well as the genomic context of the CpGs as shown by recent studies [ 53 ].…”

Section: Discussionmentioning

confidence: 99%

Interplay between Histone and DNA Methylation Seen through Comparative Methylomes in Rare Mendelian Disorders

Velasco

Ulveling

Rondeau

et al. 2021

IJMS

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DNA methylation (DNAme) profiling is used to establish specific biomarkers to improve the diagnosis of patients with inherited neurodevelopmental disorders and to guide mutation screening. In the specific case of mendelian disorders of the epigenetic machinery, it also provides the basis to infer mechanistic aspects with regard to DNAme determinants and interplay between histone and DNAme that apply to humans. Here, we present comparative methylomes from patients with mutations in the de novo DNA methyltransferases DNMT3A and DNMT3B, in their catalytic domain or their N-terminal parts involved in reading histone methylation, or in histone H3 lysine (K) methylases NSD1 or SETD2 (H3 K36) or KMT2D/MLL2 (H3 K4). We provide disease-specific DNAme signatures and document the distinct consequences of mutations in enzymes with very similar or intertwined functions, including at repeated sequences and imprinted loci. We found that KMT2D and SETD2 germline mutations have little impact on DNAme profiles. In contrast, the overlapping DNAme alterations downstream of NSD1 or DNMT3 mutations underlines functional links, more specifically between NSD1 and DNMT3B at heterochromatin regions or DNMT3A at regulatory elements. Together, these data indicate certain discrepancy with the mechanisms described in animal models or the existence of redundant or complementary functions unforeseen in humans.

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“…DNMT3a is required for the gene body methylation at Polycomb group (PcG) target developmental genes. DNMT3b has higher DNA methylation activity and hence a dominant role in the de novo methylation of X-chromosomes [19,20]. Both DNMT3a and 3b function in conjunction with a third methyltransferase, DNMT3L.…”

Section: Dna Methylationmentioning

confidence: 99%

Epigenetics in blood–brain barrier disruption

Ihezie¹,

Mathew²,

McBride³

et al. 2021

Fluids Barriers CNS

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The vessels of the central nervous system (CNS) have unique barrier properties. The endothelial cells (ECs) which comprise the CNS vessels contribute to the barrier via strong tight junctions, specific transporters, and limited endocytosis which combine to protect the brain from toxins and maintains brain homeostasis. Blood–brain barrier (BBB) leakage is a serious secondary injury in various CNS disorders like stroke, brain tumors, and neurodegenerative disorders. Currently, there are no drugs or therapeutics available to treat specifically BBB damage after a brain injury. Growing knowledge in the field of epigenetics can enhance the understanding of gene level of the BBB and has great potential for the development of novel therapeutic strategies or targets to repair a disrupted BBB. In this brief review, we summarize the epigenetic mechanisms or regulators that have a protective or disruptive role for components of BBB, along with the promising approaches to regain the integrity of BBB.

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Identification of distinct loci for de novo DNA methylation by DNMT3A and DNMT3B during mammalian development

Cited by 54 publications

References 50 publications

Cell lineage-specific methylome and genome alterations in gout

Cell lineage-specific methylome and genome alterations in gout

Interplay between Histone and DNA Methylation Seen through Comparative Methylomes in Rare Mendelian Disorders

Epigenetics in blood–brain barrier disruption

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