Circadian clock regulator Bmal1 gates axon regeneration via Tet3-5hmC mediated epigenetics
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ABSTRACT:
PROVIDER: PRJNA975965 | ENA |
REPOSITORIES: ENA
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Project description:Axon regeneration of dorsal root ganglia (DRG) neurons after peripheral axotomy involves epigenetic reconfigurations that rewire gene regulatory circuits to establish regenerative gene program. However, the mechanisms and transcriptional regulators remain poorly understood. Here, we conducted an unbiased survey of DNA differentially hydroxymethylated regions (DhMRs) in DRG after peripheral lesion, which identified enriched binding motif for Bmal1, a transcription factor and a central regulator of the circadian clock. Through applying conditional deletion of Bmal1, in vitro and in vivo models of axon regrowth, and transcriptomic profiling, we showed that Bmal1 inhibits axon regeneration in part through Tet3-dependent manner. Mechanistically, Bmal1 functions as a gatekeeper of neuroepigenetic injury responses by limiting Tet3 expression and restricting 5hmC modifications. Notably, Bmal1-regulated genes after axotomy not only concern axon guidance and axon regrowth, but also stress responses, energy homeostasis, and neuroinflammation. Furthermore, we uncovered diurnal oscillation of Tet3 and 5hmC in DRG neurons, and this epigenetic rhythm corresponded to time-of-day effect on axon growth potential. Collectively, our studies showed that Bmal1 deletion mimics the conditioning lesion in lifting epigenetic barriers to enhance axon regeneration.
2023-08-02 | GSE233367 | GEO
Project description:Axon regeneration of dorsal root ganglia (DRG) neurons after peripheral axotomy involves reconfiguration of gene regulatory circuits to establish regenerative gene programs. However, the underlying mechanisms remain unclear. Here, through an unbiased survey, we show that the binding motif of Bmal1, a central transcription factor of the circadian clock, is enriched in differentially hydroxymethylated regions (DhMRs) of mouse DRG after peripheral lesion. By applying conditional deletion of Bmal1 in neurons, in vitro and in vivo neurite outgrowth assays, as well as transcriptomic profiling, we demonstrate that Bmal1 inhibits axon regeneration, in part through a functional link with the epigenetic factor Tet3. Mechanistically, we reveal that Bmal1 acts as a gatekeeper of neuroepigenetic responses to axonal injury by limiting Tet3 expression and restricting 5hmC modifications. Bmal1-regulated genes not only concern axon growth, but also stress responses and energy homeostasis. Furthermore, we uncover an epigenetic rhythm of diurnal oscillation of Tet3 and 5hmC levels in DRG neurons, corresponding to time-of-day effect on axon growth potential. Collectively, our studies demonstrate that targeting Bmal1 enhances axon regeneration.
| S-EPMC10449865 | biostudies-literature
Project description:To examine the influences for 5hmC enrichment on genome wide after Tet3 inactivation, we determined the enrichment profiles of 5hmC, the direct demethylated target of Tet3, by hMeDIP-seq with genomic DNA from control and Tet3 inactivated lung smooth muscle cells
2021-04-30 | GSE166830 | GEO
Project description:To examine the influences for 5hmC enrichment on genome wide after Tet3 inactivation, we determined the enrichment profiles of 5hmC, the direct demethylated target of Tet3, by Nano-hmC-seq with genomic DNA from control and Tet3 inactivated lung smooth muscle cells
2022-09-21 | GSE202201 | GEO
Project description:Alzheimer's disease (AD) was attributed to alterations in multiple epigenetic systems including DNA methylation and demethylation patterns. DNA 5-hydroxymethylcytosin (5hmC), an epigenetic hallmark, plays importantly regulatory role in many biological processes. However, the 5hmC-mediated epigenetic underpinnings of AD neurodegeneration remain poorly understood. Here we report that selective loss of 5hmC is substantially presented in human AD and 3xTg-AD mouse neocortical and hippocampal neurons. Quantitative genome-wide analysis of hMeDIP-seq reveals that neuron-specific shift in decreased 5hmC enrichment in regions of promoter, intergenic and gene body of mRNA and lncRNA genes was found in3xTg-AD mice. We further identified that TET3, an enzyme that converts 5-methylcytosine (5mC) to 5hmC, responded to Beta amyloid neuronal toxicity and was mainly responsible for loss of 5hmC in AD brain. Overexpression of human TET3 catalytic domain (hTET3CD) significantly improves the neuroinflammation, neuropathological progression and cognitive deficits in 3xTg-AD mice. These findings implicate as a potential hallmark, TET3-mediated 5hmC epigenetic dysregulation is involved in driving AD neurodegeneration.
2019-02-19 | GSE126713 | GEO
Project description:DNA hydroxymethylation is frequently lost in glioblastoma. We hypothesized that reduced 5hmC levels might be related to the impaired expression of TET proteins in brain tumors. In this study we performed a genome-wide methylation analysis of LN229 cells stably transfected with scramble or TET3 overexpressing vectors. TET3 overexpression partially restored the genome-wide patterns of 5hmC characteristic of control brain samples in glioblastoma cell lines.
2018-03-03 | E-MTAB-6001 | biostudies-arrayexpress
Project description:Ten-eleven translocation (Tet) hydroxylases (Tet1-3) oxidize 5-methylcytosine (5mC) to 5-hydroxymethylcytosine (5hmC). In neurons increased 5hmC levels within gene bodies correlate positively with gene expression. The mechanisms controlling Tet activity and 5hmC levels are poorly understood. In particular, it is not known how the neuronal Tet3 isoform lacking a DNA binding domain is targeted to the DNA. To identify factors binding to Tet3 we screened for proteins that co-precipitate with Tet3 from mouse retina and identified the transcriptional repressor Rest as a highly enriched Tet3-specific interactor. Rest was able to enhance Tet3 hydroxylase activity after co-expression and overexpression of Tet3 activated transcription of Rest-target genes. Moreover, we found that Tet3 also interacts with Nsd3 and two other H3K36 methyltransferases and is able to induce H3K36 trimethylation. We propose a mechanism for transcriptional activation in neurons that involves Rest-guided targeting of Tet3 to the DNA for directed 5hmC-generation and Nsd3-mediated H3K36 trimethylation.
2015-04-02 | PXD001857 | Pride
Project description:Tet3 is an Fe2+-dependent enzyme that oxidizes genomic 5-methylcytosine to 5-hydroxymethylcytosine with the help of alpha-ketoglutarate and oxygen. It is the most abundant Tet enzyme in differentiated tissues including brain. Adult brain contains the highest 5-hydroxymethylcytosine levels. How alpha-ketoglutarate is made available for the oxidation of mC in brain cells and how the Tet activity is linked to neural activity are unsolved questions. Our experiments with full mouse brains show that Tet3 interacts in the nucleus directly with selected enzymes of the mitochondrial citric acid cycle. This leads to the formation of isocitrate. Tet3 also interacts with aspartate aminotransferase, which produces oxaloacetate. Although oxaloacetate and isocitrate are biosynthetic alpha-ketoglutarate precursors, they function as inhibitors of Tet3 and are needed to protect the reactive Fe2+ center from degrading DNA. The supply of Tet3 with alpha-ketoglutarate is established by a direct interaction of Tet3 with glutamate dehydrogenase (Glud1), which converts the neurotransmitter glutamate directly into alpha-ketoglutarate. This links Tet3 function to neural activity.
2021-05-10 | PXD004518 | Pride
Project description:TMT analysis of proteomic changes in the gastrocnemius skeletal muscles of WT and Bmal1-KO mice, and Bmal1-KO mice rescued with AAV-mediated muscle-specific expression of Bmal1.
2024-10-03 | PXD054406 | Pride
Project description:PGC7 is a primordial germ cell (PGCs)-specific protein involved in epigenetic chromatin reprogramming in the zygote following fertilization. TET3 is a dioxygenase that catalyzes the conversion of the modified genomic base 5-methylcytosine (5mC) into 5-hydroxymethylcytosine (5hmC) and plays a key role in epigenetic chromatin reprogramming in the zygote following fertilization. PGC7 participates in protection of DNA methylation in the maternal pronucleus by preventing conversion of 5mC to 5hmC by TET3 oxidization subsequent DNA demethylation. Thus we tested the co-localization of PGC7 and TET3 in specific loci by ChIP-seq assays.
2014-01-04 | E-GEOD-53809 | biostudies-arrayexpress