scholarly journals 5-Hydroxymethylcytosine-mediated active demethylation is required for mammalian neuronal differentiation and function

eLife ◽  
2021 ◽  
Vol 10 ◽  
Author(s):  
Elitsa Stoyanova ◽  
Michael Riad ◽  
Anjana Rao ◽  
Nathaniel Heintz
Keyword(s):  
Terminal Differentiation ◽  
Chromatin Accessibility ◽  
Dna Demethylation ◽  
Developmental Transitions ◽  
Regulatory Domains ◽  
Active Dna Demethylation ◽  
High Resolution Mapping ◽  
Resolution Mapping ◽  
And Function

Although high levels of 5-hydroxymethylcytosine (5hmC) accumulate in mammalian neurons, our knowledge of its roles in terminal differentiation or as an intermediate in active DNA demethylation is incomplete. We report high-resolution mapping of DNA methylation and hydroxymethylation, chromatin accessibility, and histone marks in developing postmitotic Purkinje cells (PCs) in Mus musculus. Our data reveal new relationships between PC transcriptional and epigenetic programs, and identify a class of genes that lose both 5-methylcytosine (5mC) and 5hmC during terminal differentiation. Deletion of the 5hmC writers Tet1, Tet2, and Tet3 from postmitotic PCs prevents loss of 5mC and 5hmC in regulatory domains and gene bodies, and hinders transcriptional and epigenetic developmental transitions. Our data demonstrate that Tet-mediated active DNA demethylation occurs in vivo, and that acquisition of the precise molecular properties of adult PCs require continued oxidation of 5mC to 5hmC during the final phases of differentiation.

scholarly journals 5-hydroxymethylcytosine mediated active demethylation is required for neuronal differentiation and function

2021 ◽  
Author(s):  
Elitsa Stoyanova ◽  
Michael Riad ◽  
Anjana Rao ◽  
Nathaniel Heintz
Keyword(s):  
Chromatin Accessibility ◽  
Dna Demethylation ◽  
Electrophysiological Properties ◽  
Regulatory Domains ◽  
Active Dna Demethylation ◽  
High Resolution Mapping ◽  
Resolution Mapping ◽  
And Function ◽  
Increased Susceptibility

SUMMARYAlthough high levels of 5-hydroxymethylcytosine (5hmC) accumulate in neurons, it is not known whether 5hmC can serve as an intermediate in DNA demethylation in postmitotic neurons. We report high resolution mapping of DNA methylation and hydroxymethylation, chromatin accessibility, and histone marks in developing postmitotic Purkinje cells (PCs). Our data reveal new relationships between PC transcriptional and epigenetic programs, and identify a class of genes that lose both 5mC and 5hmC during terminal differentiation. Deletion of the 5hmC writers Tet1, Tet2, and Tet3 from postmitotic PCs prevents loss of 5mC and 5hmC in regulatory domains and gene bodies and hinders transcriptional and epigenetic developmental transitions, resulting in hyper-excitability and increased susceptibility to excitotoxic drugs. Our data demonstrate that Tet-mediated active DNA demethylation occurs in vivo, and that acquisition of the precise molecular and electrophysiological properties of adult PCs requires continued oxidation of 5mC to 5hmC during the final phases of differentiation.

scholarly journals Muscle regeneration controlled by a designated DNA dioxygenase

2021 ◽  
Vol 12 (6) ◽  
Author(s):  
Hongye Wang ◽  
Yile Huang ◽  
Ming Yu ◽  
Yang Yu ◽  
Sheng Li ◽  
...  
Keyword(s):  
Muscle Regeneration ◽  
Chromatin Accessibility ◽  
Dna Demethylation ◽  
Myoblast Differentiation ◽  
Tet Proteins ◽  
Active Dna Demethylation ◽  
Mechanistic Analysis ◽  
Pioneer Transcription Factor ◽  
E Boxes

AbstractTet dioxygenases are responsible for the active DNA demethylation. The functions of Tet proteins in muscle regeneration have not been well characterized. Here we find that Tet2, but not Tet1 and Tet3, is specifically required for muscle regeneration in vivo. Loss of Tet2 leads to severe muscle regeneration defects. Further analysis indicates that Tet2 regulates myoblast differentiation and fusion. Tet2 activates transcription of the key differentiation modulator Myogenin (MyoG) by actively demethylating its enhancer region. Re-expressing of MyoG in Tet2 KO myoblasts rescues the differentiation and fusion defects. Further mechanistic analysis reveals that Tet2 enhances MyoD binding by demethylating the flanking CpG sites of E boxes to facilitate the recruitment of active histone modifications and increase chromatin accessibility and activate its transcription. These findings shed new lights on DNA methylation and pioneer transcription factor activity regulation.

scholarly journals High-Resolution Mapping of Myeloarchitecture In Vivo: Localization of Auditory Areas in the Human Brain

2014 ◽  
Vol 25 (10) ◽  
pp. 3394-3405 ◽  
Author(s):  
Federico De Martino ◽  
Michelle Moerel ◽  
Junqian Xu ◽  
Pierre-Francois van de Moortele ◽  
Kamil Ugurbil ◽  
...  
Keyword(s):  
High Resolution ◽  
Human Brain ◽  
High Resolution Mapping ◽  
Resolution Mapping

scholarly journals Epigenetic Changes Induced by Bacteroides fragilis Toxin

2019 ◽  
Vol 87 (6) ◽  
Author(s):  
Jawara Allen ◽  
Stephanie Hao ◽  
Cynthia L. Sears ◽  
Winston Timp
Keyword(s):  
Bacteroides Fragilis ◽  
Distal Colon ◽  
Chromatin Accessibility ◽  
Tumor Formation ◽  
Content Type ◽  
Intestinal Neoplasia ◽  
And Function ◽  
Gut Microbial Community ◽  
The Impact

ABSTRACT Enterotoxigenic Bacteroides fragilis (ETBF) is a Gram-negative, obligate anaerobe member of the gut microbial community in up to 40% of healthy individuals. This bacterium is found more frequently in people with colorectal cancer (CRC) and causes tumor formation in the distal colon of multiple intestinal neoplasia (Apcmin/+) mice; tumor formation is dependent on ETBF-secreted Bacteroides fragilis toxin (BFT). Because of the extensive data connecting alterations in the epigenome with tumor formation, initial experiments attempting to connect BFT-induced tumor formation with methylation in colon epithelial cells (CECs) have been performed, but the effect of BFT on other epigenetic processes, such as chromatin structure, remains unexplored. Here, the changes in gene expression (transcriptome sequencing [RNA-seq]) and chromatin accessibility (assay for transposase-accessible chromatin using sequencing) induced by treatment of HT29/C1 cells with BFT for 24 and 48 h were examined. Our data show that several genes are differentially expressed after BFT treatment and that these changes relate to the interaction between bacteria and CECs. Further, sites of increased chromatin accessibility are associated with the location of enhancers in CECs and the binding sites of transcription factors in the AP-1/ATF family; they are also enriched for common differentially methylated regions (DMRs) in CRC. These data provide insight into the mechanisms by which BFT induces tumor formation and lay the groundwork for future in vivo studies to explore the impact of BFT on nuclear structure and function.

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