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Nature Genetics Sep 2022Transcriptional regulation, which integrates chromatin accessibility, transcription factors and epigenetic modifications, is crucial for establishing and maintaining...
Transcriptional regulation, which integrates chromatin accessibility, transcription factors and epigenetic modifications, is crucial for establishing and maintaining cell identity. The interplay between different epigenetic modifications and its contribution to transcriptional regulation remains elusive. Here, we show that METTL3-mediated RNA N-methyladenosine (mA) formation leads to DNA demethylation in nearby genomic loci in normal and cancer cells, which is mediated by the interaction between mA reader FXR1 and DNA 5-methylcytosine dioxygenase TET1. Upon recognizing RNA mA, FXR1 recruits TET1 to genomic loci to demethylate DNA, leading to reprogrammed chromatin accessibility and gene transcription. Therefore, we have characterized a regulatory mechanism of chromatin accessibility and gene transcription mediated by RNA mA formation coupled with DNA demethylation, highlighting the importance of the crosstalk between RNA mA and DNA modification in physiologic and pathogenic process.
Topics: Chromatin; DNA; DNA Demethylation; DNA Methylation; RNA; Transcription Factors
PubMed: 36071173
DOI: 10.1038/s41588-022-01173-1 -
Science (New York, N.Y.) Jul 2023Methylations on nucleosomal histones play fundamental roles in regulating eukaryotic transcription. Jumonji C domain-containing histone demethylases (JMJs) dynamically...
Methylations on nucleosomal histones play fundamental roles in regulating eukaryotic transcription. Jumonji C domain-containing histone demethylases (JMJs) dynamically control the level of histone methylations. However, how JMJ activity is generally regulated is unknown. We found that the tricarboxylic acid cycle-associated enzyme α-ketoglutarate (α-KG) dehydrogenase (KGDH) entered the nucleus, where it interacted with various JMJs to regulate α-KG-dependent histone demethylations by JMJs, and thus controlled genome-wide gene expression in plants. We show that nuclear targeting is regulated by environmental signals and that KGDH is enriched at thousands of loci in . Chromatin-bound KGDH catalyzes α-KG decarboxylation and thus may limit its local availability to KGDH-coupled JMJs, inhibiting histone demethylation. Thus, our results uncover a regulatory mechanism for histone demethylations by JMJs.
Topics: Arabidopsis; Arabidopsis Proteins; Cell Nucleus; Chromatin; Demethylation; Histone Demethylases; Histones; Jumonji Domain-Containing Histone Demethylases; Ketoglutarate Dehydrogenase Complex; Gene Expression Regulation, Plant
PubMed: 37440635
DOI: 10.1126/science.adf8822 -
Science (New York, N.Y.) Dec 2022Neurons harbor high levels of single-strand DNA breaks (SSBs) that are targeted to neuronal enhancers, but the source of this endogenous damage remains unclear. Using...
Neurons harbor high levels of single-strand DNA breaks (SSBs) that are targeted to neuronal enhancers, but the source of this endogenous damage remains unclear. Using two systems of postmitotic lineage specification-induced pluripotent stem cell-derived neurons and transdifferentiated macrophages-we show that thymidine DNA glycosylase (TDG)-driven excision of methylcytosines oxidized with ten-eleven translocation enzymes (TET) is a source of SSBs. Although macrophage differentiation favors short-patch base excision repair to fill in single-nucleotide gaps, neurons also frequently use the long-patch subpathway. Disrupting this gap-filling process using anti-neoplastic cytosine analogs triggers a DNA damage response and neuronal cell death, which is dependent on TDG. Thus, TET-mediated active DNA demethylation promotes endogenous DNA damage, a process that normally safeguards cell identity but can also provoke neurotoxicity after anticancer treatments.
Topics: Cell Differentiation; DNA Demethylation; Induced Pluripotent Stem Cells; Neurons; DNA Breaks, Single-Stranded; Enhancer Elements, Genetic; Thymine DNA Glycosylase; DNA Repair; 5-Methylcytosine; Humans; Cell Transdifferentiation
PubMed: 36454826
DOI: 10.1126/science.add9838 -
Molecular Therapy : the Journal of the... Jul 2022Cancer cells respond to various stressful conditions through the dynamic regulation of RNA m6A modification. Doxorubicin is a widely used chemotherapeutic drug that...
Cancer cells respond to various stressful conditions through the dynamic regulation of RNA m6A modification. Doxorubicin is a widely used chemotherapeutic drug that induces DNA damage. It is interesting to know whether cancer cells regulate the DNA damage response and doxorubicin sensitivity through RNA m6A modification. Here, we found that doxorubicin treatment significantly induced RNA m6A methylation in breast cancer cells in both a dose- and a time-dependent manner. However, protein arginine methyltransferase 5 (PRMT5) inhibited RNA m6A modification under doxorubicin treatment by enhancing the nuclear translocation of the RNA demethylase AlkB homolog 5 (ALKBH5), which was previously believed to be exclusively localized in the nucleus. Then, ALKBH5 removed the m6A methylation of BRCA1 for mRNA stabilization and further enhanced DNA repair competency to decrease doxorubicin efficacy in breast cancer cells. Importantly, we identified the approved drug tadalafil as a novel PRMT5 inhibitor that could decrease RNA m6A methylation and increase doxorubicin sensitivity in breast cancer. The strategy of targeting PRMT5 with tadalafil is a promising approach to promote breast cancer sensitivity to doxorubicin through RNA methylation regulation.
Topics: Breast Neoplasms; Demethylation; Doxorubicin; Female; Humans; Protein-Arginine N-Methyltransferases; RNA; Tadalafil
PubMed: 35278676
DOI: 10.1016/j.ymthe.2022.03.003 -
Molecular Cell Sep 2018FTO, the first RNA demethylase discovered, mediates the demethylation of internal N-methyladenosine (mA) and N, 2-O-dimethyladenosine (mA) at the +1 position from the...
FTO, the first RNA demethylase discovered, mediates the demethylation of internal N-methyladenosine (mA) and N, 2-O-dimethyladenosine (mA) at the +1 position from the 5' cap in mRNA. Here we demonstrate that the cellular distribution of FTO is distinct among different cell lines, affecting the access of FTO to different RNA substrates. We find that FTO binds multiple RNA species, including mRNA, snRNA, and tRNA, and can demethylate internal mA and cap mA in mRNA, internal mA in U6 RNA, internal and cap mA in snRNAs, and N-methyladenosine (mA) in tRNA. FTO-mediated demethylation has a greater effect on the transcript levels of mRNAs possessing internal mA than the ones with cap mA in the tested cells. We also show that FTO can directly repress translation by catalyzing mA tRNA demethylation. Collectively, FTO-mediated RNA demethylation occurs to mA and mA in mRNA and snRNA as well as mA in tRNA.
Topics: 3T3-L1 Cells; Adenosine; Alpha-Ketoglutarate-Dependent Dioxygenase FTO; Animals; Cell Nucleus; Cytoplasm; Demethylation; Gene Expression; HEK293 Cells; HeLa Cells; Humans; Methylation; Mice; RNA Processing, Post-Transcriptional; RNA, Messenger; RNA, Small Nuclear; RNA, Transfer
PubMed: 30197295
DOI: 10.1016/j.molcel.2018.08.011 -
Nature Chemical Biology Aug 2023
Topics: DNA Methylation; Demethylation
PubMed: 37500897
DOI: 10.1038/s41589-023-01398-z -
Nature Cell Biology Oct 2023All eukaryotic cells require a minimal iron threshold to sustain anabolic metabolism. However, the mechanisms by which cells sense iron to regulate anabolic processes...
All eukaryotic cells require a minimal iron threshold to sustain anabolic metabolism. However, the mechanisms by which cells sense iron to regulate anabolic processes are unclear. Here we report a previously undescribed eukaryotic pathway for iron sensing in which molecular iron is required to sustain active histone demethylation and maintain the expression of critical components of the pro-anabolic mTORC1 pathway. Specifically, we identify the iron-binding histone-demethylase KDM3B as an intrinsic iron sensor that regulates mTORC1 activity by demethylating H3K9me at enhancers of a high-affinity leucine transporter, LAT3, and RPTOR. By directly suppressing leucine availability and RAPTOR levels, iron deficiency supersedes other nutrient inputs into mTORC1. This process occurs in vivo and is not an indirect effect by canonical iron-utilizing pathways. Because ancestral eukaryotes share homologues of KDMs and mTORC1 core components, this pathway probably pre-dated the emergence of the other kingdom-specific nutrient sensors for mTORC1.
Topics: Mechanistic Target of Rapamycin Complex 1; Leucine; Histones; Signal Transduction; Iron; Regulatory-Associated Protein of mTOR; Demethylation
PubMed: 37749225
DOI: 10.1038/s41556-023-01225-6 -
Neuro-oncology May 2022
Topics: DNA; Demethylation; Glioma; Humans; Isocitrate Dehydrogenase; Tretinoin
PubMed: 35239963
DOI: 10.1093/neuonc/noac056 -
Nature Biotechnology Dec 2021RNA N-methyladenosine (mA) modifications are essential in plants. Here, we show that transgenic expression of the human RNA demethylase FTO in rice caused a more than...
RNA N-methyladenosine (mA) modifications are essential in plants. Here, we show that transgenic expression of the human RNA demethylase FTO in rice caused a more than threefold increase in grain yield under greenhouse conditions. In field trials, transgenic expression of FTO in rice and potato caused ~50% increases in yield and biomass. We demonstrate that the presence of FTO stimulates root meristem cell proliferation and tiller bud formation and promotes photosynthetic efficiency and drought tolerance but has no effect on mature cell size, shoot meristem cell proliferation, root diameter, plant height or ploidy. FTO mediates substantial mA demethylation (around 7% of demethylation in poly(A) RNA and around 35% decrease of mA in non-ribosomal nuclear RNA) in plant RNA, inducing chromatin openness and transcriptional activation. Therefore, modulation of plant RNA mA methylation is a promising strategy to dramatically improve plant growth and crop yield.
Topics: Alpha-Ketoglutarate-Dependent Dioxygenase FTO; Biomass; Demethylation; Humans; Oryza; Plants, Genetically Modified; RNA, Plant; Solanum tuberosum
PubMed: 34294912
DOI: 10.1038/s41587-021-00982-9 -
Journal of Advanced Research Dec 2023Poor wound healing is a significant complication of diabetes, which is commonly caused by neuropathy, trauma, deformities, plantar hypertension and peripheral arterial... (Review)
Review
BACKGROUND
Poor wound healing is a significant complication of diabetes, which is commonly caused by neuropathy, trauma, deformities, plantar hypertension and peripheral arterial disease. Diabetic foot ulcers (DFU) are difficult to heal, which makes patients susceptible to infections and can ultimately conduce to limb amputation or even death in severe cases. An increasing number of studies have found that epigenetic alterations are strongly associated with poor wound healing in diabetes.
AIM OF REVIEW
This work provides significant insights into the development of therapeutics for improving chronic diabetic wound healing, particularly by targeting and regulating DNA methylation and demethylation in DFU. Key scientific concepts of review: DNA methylation and demethylation play an important part in diabetic wound healing, via regulating corresponding signaling pathways in different breeds of cells, including macrophages, vascular endothelial cells and keratinocytes. In this review, we describe the four main phases of wound healing and their abnormality in diabetic patients. Furthermore, we provided an in-depth summary and discussion on how DNA methylation and demethylation regulate diabetic wound healing in different types of cells; and gave a brief summary on recent advances in applying cellular reprogramming techniques for improving diabetic wound healing.
Topics: Humans; Diabetic Foot; DNA Methylation; Endothelial Cells; Wound Healing; Demethylation; Diabetes Mellitus
PubMed: 36706989
DOI: 10.1016/j.jare.2023.01.009