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 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 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.

Pax3 and Pax7 expression during myoblast differentiation in vitro and fast and slow muscle regeneration in vivo

2009 ◽  
Vol 33 (4) ◽  
pp. 483-492 ◽  
Author(s):  
Edyta Brzóska ◽  
Marta Przewoźniak ◽  
Iwona Grabowska ◽  
Katarzyna Jańczyk-Ilach ◽  
Jerzy Moraczewski
Keyword(s):  
Muscle Regeneration ◽  
Slow Muscle ◽  
Myoblast Differentiation ◽  
Fast And Slow Muscle

scholarly journals Vitamin C Transporters and Their Implications in Carcinogenesis

Nutrients ◽  
2020 ◽  
Vol 12 (12) ◽  
pp. 3869
Author(s):  
Kinga Linowiecka ◽  
Marek Foksinski ◽  
Anna A. Brożyna
Keyword(s):  
Vitamin C ◽  
Cancer Biology ◽  
Redox Homeostasis ◽  
Regulation Of Gene Expression ◽  
Dna Demethylation ◽  
Altered Expression ◽  
Tet Proteins ◽  
Active Dna Demethylation ◽  
Hypoxic State

Vitamin C is implicated in various bodily functions due to its unique properties in redox homeostasis. Moreover, vitamin C also plays a great role in restoring the activity of 2-oxoglutarate and Fe2+ dependent dioxygenases (2-OGDD), which are involved in active DNA demethylation (TET proteins), the demethylation of histones, and hypoxia processes. Therefore, vitamin C may be engaged in the regulation of gene expression or in a hypoxic state. Hence, vitamin C has acquired great interest for its plausible effects on cancer treatment. Since its conceptualization, the role of vitamin C in cancer therapy has been a controversial and disputed issue. Vitamin C is transferred to the cells with sodium dependent transporters (SVCTs) and glucose transporters (GLUT). However, it is unknown whether the impaired function of these transporters may lead to carcinogenesis and tumor progression. Notably, previous studies have identified SVCTs’ polymorphisms or their altered expression in some types of cancer. This review discusses the potential effects of vitamin C and the impaired SVCT function in cancers. The variations in vitamin C transporter genes may regulate the active transport of vitamin C, and therefore have an impact on cancer risk, but further studies are needed to thoroughly elucidate their involvement in cancer biology.

scholarly journals Tet-Mediated Formation of 5-Carboxylcytosine and Its Excision by TDG in Mammalian DNA

Science ◽  
2011 ◽  
Vol 333 (6047) ◽  
pp. 1303-1307 ◽  
Author(s):  
Yu-Fei He ◽  
Bin-Zhong Li ◽  
Zheng Li ◽  
Peng Liu ◽  
Yang Wang ◽  
...  
Keyword(s):  
Stem Cells ◽  
Cultured Cells ◽  
Dna Demethylation ◽  
Detectable Level ◽  
Dna Modification ◽  
Thymine Dna Glycosylase ◽  
Tet Proteins ◽  
Active Dna Demethylation ◽  
Base Excision

The prevalent DNA modification in higher organisms is the methylation of cytosine to 5-methylcytosine (5mC), which is partially converted to 5-hydroxymethylcytosine (5hmC) by the Tet (ten eleven translocation) family of dioxygenases. Despite their importance in epigenetic regulation, it is unclear how these cytosine modifications are reversed. Here, we demonstrate that 5mC and 5hmC in DNA are oxidized to 5-carboxylcytosine (5caC) by Tet dioxygenases in vitro and in cultured cells. 5caC is specifically recognized and excised by thymine-DNA glycosylase (TDG). Depletion of TDG in mouse embyronic stem cells leads to accumulation of 5caC to a readily detectable level. These data suggest that oxidation of 5mC by Tet proteins followed by TDG-mediated base excision of 5caC constitutes a pathway for active DNA demethylation.

scholarly journals Epigenetic reprogramming in the germline: towards the ground state of the epigenome

2011 ◽  
Vol 366 (1575) ◽  
pp. 2266-2273 ◽  
Author(s):  
Petra Hajkova
Keyword(s):  
Cell Fate ◽  
Dna Demethylation ◽  
Epigenetic Reprogramming ◽  
Developmental Model ◽  
Active Dna Demethylation ◽  
Base Excision ◽  
Base Excision Dna Repair ◽  
Regeneration Systems

Epigenetic reprogramming in the germline provides a developmental model to study the erasure of epigenetic memory as it occurs naturally in vivo in the course of normal embryonic development. Our data show that germline reprogramming comprises both active DNA demethylation and extensive chromatin remodelling that are mechanistically linked through the activation of the base excision DNA repair pathway involved in the DNA demethylation process. The observed molecular hallmarks of the germline reprogramming exhibit intriguing similarities to other dedifferentiation or regeneration systems, pointing towards the existence of unifying molecular pathways underlying cell fate reversal. Elucidation of molecular processes involved in the resetting of epigenetic information in vivo will thus add to our ability to manipulate cell fate and to restore pluripotency in in vitro settings.

scholarly journals LEAFY is a pioneer transcription factor and licenses cell reprogramming to floral fate

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Run Jin ◽  
Samantha Klasfeld ◽  
Yang Zhu ◽  
Meilin Fernandez Garcia ◽  
Jun Xiao ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Transcription Factors ◽  
Cell Fate ◽  
Chromatin Accessibility ◽  
Binding Motifs ◽  
Chromatin Remodelers ◽  
Pioneer Transcription Factor ◽  
Chromatin Reprogramming

AbstractMaster transcription factors reprogram cell fate in multicellular eukaryotes. Pioneer transcription factors have prominent roles in this process because of their ability to contact their cognate binding motifs in closed chromatin. Reprogramming is pervasive in plants, whose development is plastic and tuned by the environment, yet little is known about pioneer transcription factors in this kingdom. Here, we show that the master transcription factor LEAFY (LFY), which promotes floral fate through upregulation of the floral commitment factor APETALA1 (AP1), is a pioneer transcription factor. In vitro, LFY binds to the endogenous AP1 target locus DNA assembled into a nucleosome. In vivo, LFY associates with nucleosome occupied binding sites at the majority of its target loci, including AP1. Upon binding, LFY ‘unlocks’ chromatin locally by displacing the H1 linker histone and by recruiting SWI/SNF chromatin remodelers, but broad changes in chromatin accessibility occur later. Our study provides a mechanistic framework for patterning of inflorescence architecture and uncovers striking similarities between LFY and animal pioneer transcription factor.

scholarly journals Human Reproduction is Regulated by Retrotransposons derived from Ancient Hominin-Specific Viral Infections

2020 ◽  
Author(s):  
Yu Tao ◽  
Xiinyu Xiang ◽  
Fei-Man Hsu ◽  
Julien Pontis ◽  
Didier Trono ◽  
...  
Keyword(s):  
Germ Cells ◽  
Viral Infections ◽  
Primordial Germ Cells ◽  
Embryonic Stem ◽  
Chromatin Accessibility ◽  
Dna Demethylation ◽  
Human Reproduction ◽  
Epigenetic Landscape

Abstract Germ cells are essential to pass DNA from one generation to the next. In human reproduction, germ cell development begins with the specification of primordial germ cells (PGCs) and a failure to specify PGCs leads to human infertility. Recent studies have revealed that the transcription factor network required for PGC specification has diverged in mammals, and this has a significant impact on our understanding of human reproduction. Here, we evaluated the emerging epigenetic landscape during hPGC specification using a combination of in vivo and in vitro analysis of hPGCs/hPGC-like cells (hPGCLCs) and human embryonic stem cells (hESCs). Our data reveals that hominid restricted Transposable Elements (TEs) partly derived from ancient viruses are pre-bound by the transcription factors TFAP2C and NANOG in undifferentiated hESCs, become transcriptionally induced during PGC specification and undergo dynamic epigenetic reprogramming leading to increased chromatin accessibility, localized DNA demethylation and establishment of broad peaks of H3K27ac. Using KRAB mediated CRISPRi we show that blocking this remodeling has a significant impact on hPGC specification. In summary, our data reveals that human reproduction requires the establishment of an epigenetic landscape during hPGC specification driven by the acquisition of hominid-specific TEs that were derived from ancient viral infections that entered the hominid germline less than 5 million years ago.

scholarly journals Itaconate Inhibits TET DNA Dioxygenases to Dampen Inflammatory Responses

2021 ◽  
Author(s):  
Dan Ye ◽  
Leilei Chen ◽  
Carmen Morcelle ◽  
Zhouli Cheng ◽  
Xiufei Chen ◽  
...  
Keyword(s):  
Catalytic Activity ◽  
Inflammatory Responses ◽  
Aerobic Glycolysis ◽  
Dna Demethylation ◽  
Metabolic Reprogramming ◽  
Immune Response Gene ◽  
Metabolic Enzyme ◽  
Active Dna Demethylation ◽  
Anti Inflammatory

Abstract The immune-response gene 1 (IRG1) plays a key role in anti-pathogen defense, as deletion of Irg1 in mice causes severe defects in response to bacterial and viral infection, and decreased survival1, 2. IRG1 transcription is rapidly induced by pathogen infection and inflammatory conditions primarily in cells of myeloid lineage3. IRG1 encodes a mitochondrial metabolic enzyme, aconitate decarboxylase 1 (ACOD1), that catalyzes the decarboxylation of cis-aconitate to produce the anti-inflammatory metabolite itaconic acid (ITA)4. Several molecular processes are affected by ITA, including succinate dehydrogenase (SDH) inhibition5, resulting in succinate accumulation and metabolic reprogramming6, 7, and alkylation of protein cysteine residues, inducing the electrophilic stress response mediated by NRF2 and IκBζ8, 9 and impairing aerobic glycolysis10. However, the mechanisms by which ITA exerts its profound anti-inflammatory effect still remains to be fully elucidated. Here, we show that ITA is a potent inhibitor of the TET family DNA dioxygenases, which catalyze the conversion of 5-methylcytosine (5mC) to 5-hydroxymethylcytosine (5hmC) during the process of active DNA demethylation. ITA binds to the same site of α-ketoglutarate (α-KG) in TET2, inhibiting its catalytic activity. Lipopolysaccharides (LPS) treatment, which induces Irg1 expression and ITA accumulation, inhibits Tet activity in macrophages. Transcriptome analysis reveals TET2 is a major target of ITA in suppressing LPS-induced genes, including those regulated by NF-κB and STAT signaling pathways. In vivo, ITA decreases 5hmC, reduces LPS-induced acute pulmonary edema and lung and liver injury, and protects mice against lethal endotoxaemia in a manner that is dependent on the catalytic activity of Tet2. Our study thus identifies ITA as an immune modulatory metabolite that selectively inhibits TET enzymes to dampen the inflammatory response.

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