DNA methylation in disease: Immunodeficiency, Centromeric instability, Facial anomalies syndrome

Vukić, Maja; Daxinger, Lucia

doi:10.1042/ebc20190035

Cited by 45 publications

(30 citation statements)

References 113 publications

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“…As a key epigenetic modification, DNA methylation has been widely studied to investigate its role in the etiology of several diseases, including FASD (Cobben et al, 2019; Robertson, 2005; Vukic and Daxinger, 2019). Methylation encodes information not by affecting DNA sequences, but by influencing regulatory protein binding to target sites, which in turn controls nucleosome structure and chromatin accessibility.…”

Section: Discussionmentioning

confidence: 99%

Glutathione Protects the Developing Heart from Defects and Global DNA Hypomethylation Induced by Prenatal Alcohol Exposure

Jawaid

Strainic

Kim

et al. 2021

Alcoholism Clin & Exp Res

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Background Fetal alcohol spectrum disorder (FASD) is caused by prenatal alcohol exposure (PAE), the intake of ethanol (C2H5OH) during pregnancy. Features of FASD cover a range of structural and functional defects including congenital heart defects (CHDs). Folic acid and choline, contributors of methyl groups to one‐carbon metabolism (OCM), prevent CHDs in humans. Using our avian model of FASD, we have previously reported that betaine, another methyl donor downstream of choline, prevents CHDs. The CHD preventions are substantial but incomplete. Ethanol causes oxidative stress as well as depleting methyl groups for OCM to support DNA methylation and other epigenetic alterations. To identify more compounds that can safely and effectively prevent CHDs and other effects of PAE, we tested glutathione (GSH), a compound that regulates OCM and is known as a “master antioxidant.” Methods/Results Quail embryos injected with a single dose of ethanol at gastrulation exhibited congenital defects including CHDs similar to those identified in FASD individuals. GSH injected simultaneously with ethanol not only prevented CHDs, but also improved survival and prevented other PAE‐induced defects. Assays of hearts at 8 days (HH stage 34) of quail development, when the heart normally has developed 4‐chambers, showed that this single dose of PAE reduced global DNA methylation. GSH supplementation concurrent with PAE normalized global DNA methylation levels. The same assays performed on quail hearts at 3 days (HH stage 19‐20) of development, showed no difference in global DNA methylation between controls, ethanol‐treated, GSH alone, and GSH plus ethanol‐treated cohorts. Conclusions GSH supplementation shows promise to inhibit effects of PAE by improving survival, reducing the incidence of morphological defects including CHDs, and preventing global hypomethylation of DNA in heart tissues.

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Section: Discussionmentioning

confidence: 99%

Glutathione Protects the Developing Heart from Defects and Global DNA Hypomethylation Induced by Prenatal Alcohol Exposure

Jawaid

Strainic

Kim

et al. 2021

Alcoholism Clin & Exp Res

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“…ICF syndrome is associated with defects in DNA methylation manifested by hypomethylation of pericentromeric satellite repeats ( Vukic and Daxinger, 2019 ). Thus, besides its direct role in c-NHEJ, ZBTB24 may also regulate CSR indirectly as an epigenetic modifier.…”

Section: Discussionmentioning

confidence: 99%

“…Thus, besides its direct role in c-NHEJ, ZBTB24 may also regulate CSR indirectly as an epigenetic modifier. ZBTB24 regulates genome-wide DNMT1-dependent DNA methylation, which has been shown to alter transcription programs ( Vukic and Daxinger, 2019 ; Wu et al, 2016 ). This could potentially affect the expression of genes involved in B cell development and the transcriptional status of CSR machinery ( Lee and Maeda, 2012 ).…”

Section: Discussionmentioning

confidence: 99%

Loss of ZBTB24 impairs nonhomologous end-joining and class-switch recombination in patients with ICF syndrome

Helfricht

Thijssen

Rother

et al. 2020

Journal of Experimental Medicine

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The autosomal recessive immunodeficiency, centromeric instability, and facial anomalies (ICF) syndrome is a genetically heterogeneous disorder. Despite the identification of the underlying gene defects, it is unclear how mutations in any of the four known ICF genes cause a primary immunodeficiency. Here we demonstrate that loss of ZBTB24 in B cells from mice and ICF2 patients affects nonhomologous end-joining (NHEJ) during immunoglobulin class-switch recombination and consequently impairs immunoglobulin production and isotype balance. Mechanistically, we found that ZBTB24 associates with poly(ADP-ribose) polymerase 1 (PARP1) and stimulates its auto-poly(ADP-ribosyl)ation. The zinc-finger in ZBTB24 binds PARP1-associated poly(ADP-ribose) chains and mediates the PARP1-dependent recruitment of ZBTB24 to DNA breaks. Moreover, through its association with poly(ADP-ribose) chains, ZBTB24 protects them from degradation by poly(ADP-ribose) glycohydrolase (PARG). This facilitates the poly(ADP-ribose)-dependent assembly of the LIG4/XRCC4 complex at DNA breaks, thereby promoting error-free NHEJ. Thus, we uncover ZBTB24 as a regulator of PARP1-dependent NHEJ and class-switch recombination, providing a molecular basis for the immunodeficiency in ICF2 syndrome.

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“…Here, Zbtb24 loss can result in transcriptional repression and aberrant DNA methylation gain. Relevant to this, mutations in ZBTB24 underlie ICF syndrome, a disease characterized by alterations in the DNA methylation landscape (Vukic and Daxinger 2019). Intriguingly, ZBTB24 has thousands of binding sites in somatic HCT116 cells and they are enriched for CpG-rich promoters of actively transcribed genes (Thompson et al 2018).…”

Section: Discussionmentioning

confidence: 99%

Zbtb24 binding protects promoter activity by antagonizing DNA methylation in mESCs

Hao

Vukić

et al. 2019

Preprint

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DNA methylation is a key epigenetic modification essential for normal development. How particular factors control DNA methylation patterns and activity of a given locus is incompletely understood. The zinc finger protein Zbtb24 has been implicated in transcriptional activation/repression and the DNA methylation maintenance pathway. Here, using whole genome bisulfite sequencing in mouse embryonic stem cells, we report that besides a general trend towards DNA hypomethylation, many genomic sites gain methylation in the absence of Zbtb24 and they include promoters of actively transcribed genes. DNA hypomethylation is not generally associated with gene expression changes, suggesting that additional epigenetic safeguards are in place that ensure silencing of the affected loci. Remarkably, we identify a set 2 of genes that is particularly susceptible to Zbtb24 occupancy. At these sites, Zbtb24 binding is not only required for gene activity but also required for maintaining the unmethylated state of the promoter.

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DNA methylation in disease: Immunodeficiency, Centromeric instability, Facial anomalies syndrome

Cited by 45 publications

References 113 publications

Glutathione Protects the Developing Heart from Defects and Global DNA Hypomethylation Induced by Prenatal Alcohol Exposure

Glutathione Protects the Developing Heart from Defects and Global DNA Hypomethylation Induced by Prenatal Alcohol Exposure

Loss of ZBTB24 impairs nonhomologous end-joining and class-switch recombination in patients with ICF syndrome

Zbtb24 binding protects promoter activity by antagonizing DNA methylation in mESCs

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