DNA methylation, a hand behind neurodegenerative diseases

Lu, Haoyang; Liu, Xinzhou; Y, Deng; Qing, Hong

doi:10.3389/fnagi.2013.00085

Cited by 145 publications

(96 citation statements)

References 148 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…The relevance of proximal PLAT promoter methylation in various physiological and pathological conditions needs to be established in specifically designed studies that address each condition. This will require PLAT gene methylation analysis in the different cell types that contribute to local t-PA concentrations in physiological and pathological conditions such as diabetes [51,52] or neurodegenerative diseases [53,54], while taking into account environmental factors such as diet [55], exercise [56] or other relevant factors.…”

Section: Discussionmentioning

confidence: 99%

Effect of Regulatory Element DNA Methylation on Tissue-Type Plasminogen Activator Gene Expression

et al. 2016

View full text Add to dashboard Cite

Expression of the tissue-type plasminogen activator gene (t-PA; gene name PLAT) is regulated, in part, by epigenetic mechanisms. We investigated the relationship between PLAT methylation and PLAT expression in five primary human cell types and six transformed cell lines. CpG methylation was analyzed in the proximal PLAT gene promoter and near the multihormone responsive enhancer (MHRE) -7.3 kilobase pairs upstream of the PLAT transcriptional start site (TSS, -7.3 kb). In Bowes melanoma cells, the PLAT promoter and the MHRE were fully unmethylated and t-PA secretion was extremely high. In other cell types the region from -647 to -366 was fully methylated, whereas an unmethylated stretch of DNA from -121 to +94 was required but not sufficient for detectable t-PA mRNA and t-PA secretion. DNA methylation near the MHRE was not correlated with t-PA secretion. Specific methylation of the PLAT promoter region -151 to +151, inserted into a firefly luciferase reporter gene, abolished reporter gene activity. The region -121 to + 94 contains two well-described regulatory elements, a PMA-responsive element (CRE) near -106 and a GC-rich region containing an Sp1 binding site near +59. Methylation of double-stranded DNA oligonucleotides containing the CRE or the GC-rich region had little or no effect on transcription factor binding. Methylated CpGs may attract co-repressor complexes that contain histone deacetylases (HDAC). However, reporter gene activity of methylated plasmids was not restored by the HDAC inhibitor trichostatin. In conclusion, efficient PLAT gene expression requires a short stretch of unmethylated CpG sites in the proximal promoter.

show abstract

Section: Discussionmentioning

confidence: 99%

Effect of Regulatory Element DNA Methylation on Tissue-Type Plasminogen Activator Gene Expression

et al. 2016

View full text Add to dashboard Cite

show abstract

“…Such phenotypic variation is believed to be the result of modifier genes, but it can also arise from different epitypes, which defines unique epigenetic status at different location for each individual, and influence disease progression and penetrance. While expanded repeats have been shown to modify the epitype in other diseases 3 , other factors, including environmental exposure to toxins, diet, and aging, are all known to influence epigenetic changes 19,20 and might in turn act as disease modifiers. Interestingly, levels of proteins involved in methylation processes, such as DNMT1, DNMT3a, and 5-methylcytosine, have all been reported to be up-regulated in motor neurons of ALS patients 21 .…”

Section: Discussionmentioning

confidence: 99%

Characterization of DNA hypermethylation in the cerebellum of c9FTD/ALS patients

et al. 2014

View full text Add to dashboard Cite

“…First, up-regulation of IAP elements and global DNA demethylation have been associated with neurodegenerative and neuroinflammatory diseases (Perron and Lang 2010;Lu et al 2013). Furthermore, overexpression of a human ERV, HERV-K, is sufficient to cause neurodegeneration .…”

Section: Postnatal Neurodegeneration In Uhrf1 Ckosmentioning

confidence: 99%

Loss of Uhrf1 in neural stem cells leads to activation of retroviral elements and delayed neurodegeneration

et al. 2016

View full text Add to dashboard Cite

In order to understand whether early epigenetic mechanisms instruct the long-term behavior of neural stem cells (NSCs) and their progeny, we examined Uhrf1 (ubiquitin-like PHD ring finger-1; also known as Np95), as it is highly expressed in NSCs of the developing brain and rapidly down-regulated upon differentiation. Conditional deletion of Uhrf1 in the developing cerebral cortex resulted in rather normal proliferation and neurogenesis but severe postnatal neurodegeneration. During development, deletion of Uhrf1 lead to global DNA hypomethylation with a strong activation of the intracisternal A particle (IAP) family of endogenous retroviral elements, accompanied by an increase in 5-hydroxymethylcytosine. Down-regulation of Tet enzymes rescued the IAP activation in Uhrf1 conditional knockout (cKO) cells, suggesting an antagonistic interplay between Uhrf1 and Tet on IAP regulation. As IAP up-regulation persists into postnatal stages in the Uhrf1 cKO mice, our data show the lack of means to repress IAPs in differentiating neurons that normally never express Uhrf1. The high load of viral proteins and other transcriptional deregulation ultimately led to postnatal neurodegeneration. Taken together, these data show that early developmental NSC factors can have long-term effects in neuronal differentiation and survival. Moreover, they highlight how specific the consequences of widespread changes in DNA methylation are for certain classes of retroviral elements. Neurogenesis is a complex process comprising several critical steps from proliferation of stem and progenitor cells to their differentiation and maturation into neurons. Each step of the neurogenic cascade is under tight transcriptional and post-transcriptional control and needs to be coordinated with the next differentiation step. Several transcription factors have been identified with key roles in specifying neurogenic fate in neural stem or progenitor cells, such as proneural factors Ascl1 and Ngn2, homeobox transcription factors Pax6 and Dlx, and many others (Schuurmans and Guillemot 2002;Wilkinson et al. 2013). These factors have early effects on neural stem cell (NSC) behavior and neurogenesis via transcriptional regulation. However, much less is known regarding whether and how mechanisms acting early in NSCs may exert effects only at later stages of neuronal differentiation or on postnatal gliogenesis. One of the key questions lies in unraveling the extent to which factors present at early developmental stages leave long-lasting traces on transcriptional regulation, affecting late stages of neuronal differentiation.One mechanism by which gene regulation is modulated is via epigenetic modifications, such as DNA methylation (Tyssowski et al. 2014). DNA methylation is carried out by the Dnmt group of methyltransferases: Dnmt1, Dnmt3a, and Dnmt3b. Dnmt3 enzymes are de novo methyltransferases, whereas Dnmt1 is largely involved in maintaining DNA methylation in somatic cycling cells. DNA methylation modulates the expression of

show abstract

DNA methylation, a hand behind neurodegenerative diseases

Cited by 145 publications

References 148 publications

Effect of Regulatory Element DNA Methylation on Tissue-Type Plasminogen Activator Gene Expression

Effect of Regulatory Element DNA Methylation on Tissue-Type Plasminogen Activator Gene Expression

Characterization of DNA hypermethylation in the cerebellum of c9FTD/ALS patients

Loss of Uhrf1 in neural stem cells leads to activation of retroviral elements and delayed neurodegeneration

Contact Info

Product

Resources

About