The mechanisms regulating myelin repair in the adult central nervous system (CNS) are unclear. Here, we identify DNA hydroxymethylation, catalyzed by the Ten-Eleven-Translocation (TET) enzyme TET1, as necessary for myelin repair in young adults and defective in old mice. Constitutive and inducible oligodendrocyte lineage-specific ablation of Tet1 (but not of Tet2), recapitulate this age-related decline in repair of demyelinated lesions. DNA hydroxymethylation and transcriptomic analyses identify TET1-target in adult oligodendrocytes, as genes regulating neuro-glial communication, including the solute carrier (Slc) gene family. Among them, we show that the expression levels of the Na+/K+/Cl− transporter, SLC12A2, are higher in Tet1 overexpressing cells and lower in old or Tet1 knockout. Both aged mice and Tet1 mutants also present inefficient myelin repair and axo-myelinic swellings. Zebrafish mutants for slc12a2b also display swellings of CNS myelinated axons. Our findings suggest that TET1 is required for adult myelin repair and regulation of the axon-myelin interface.
Highlights:-DNA hydroxy-methylation (5hmC) regulates gene expression in adult OPC (aOPC) -TET1, the enzyme catalyzing 5hmC in aOPC regulates myelin regenerative potential -Age-related TET1 decline results in decreased 5hmC and inefficient remyelination -Tet1 loss in aOPC impairs solute carrier expression and mimics remyelination in aging SummaryAdult myelination is essential for brain function and response to injury, but the molecular mechanisms remain elusive. Here we identify DNA hydroxy-methylation, an epigenetic mark catalyzed by Ten-Eleven translocation (TET) enzymes, as necessary for adult myelin repair.While DNA hydroxy-methylation and high levels of TET1 are detected in young adult mice during myelin regeneration after demyelination, this process is defective in old mice. Constitutive or inducible lineage-specific ablation of Tet1 (but not of Tet2) recapitulate the age-related decline of DNA hydroxy-methylation and inefficient remyelination. Genome-wide hydroxy-methylation and transcriptomic analysis identify numerous TET1 targets, including several members of the solute carrier (Slc) gene family. Lower transcripts for Slc genes, including Slc12a2, are observed in Tet1 mutants and old mice and are associated with swelling at the neuroglial interface, a phenotype detected also in zebrafish slc12a2b mutants.We conclude that TET1-mediated DNA hydroxy-methylation is necessary for adult myelination after injury.
Harmful alcohol use is a leading cause of premature death and is associated with age‐related disease. Biological ageing is highly variable between individuals and may deviate from chronological ageing, suggesting that biomarkers of biological ageing (derived from DNA methylation or brain structural measures) may be clinically relevant. Here, we investigated the relationships between alcohol phenotypes and both brain and DNA methylation age estimates. First, using data from UK Biobank and Generation Scotland, we tested the association between alcohol consumption (units/week) or hazardous use (Alcohol Use Disorders Identification Test [AUDIT] scores) and accelerated brain and epigenetic ageing in 20,258 and 8051 individuals, respectively. Second, we used Mendelian randomisation (MR) to test for a causal effect of alcohol consumption levels and alcohol use disorder (AUD) on biological ageing. Alcohol use showed a consistent positive association with higher predicted brain age (AUDIT‐C: β = 0.053, p = 3.16 × 10−13; AUDIT‐P: β = 0.052, p = 1.6 × 10−13; total AUDIT score: β = 0.062, p = 5.52 × 10−16; units/week: β = 0.078, p = 2.20 × 10−16), and two DNA methylation‐based estimates of ageing, GrimAge (units/week: β = 0.053, p = 1.48 × 10−7) and PhenoAge (units/week: β = 0.077, p = 2.18x10−10). MR analyses revealed limited evidence for a causal effect of AUD on accelerated brain ageing (β = 0.118, p = 0.044). However, this result should be interpreted cautiously as the significant effect was driven by a single genetic variant. We found no evidence for a causal effect of alcohol consumption levels on accelerated biological ageing. Future studies investigating the mechanisms associating alcohol use with accelerated biological ageing are warranted.
The myelinated white matter tracts of the central nervous system (CNS) are essential for fast transmission of electrical impulses and are commonly affected in neurodegenerative diseases. However, these often uniquely human diseases differentially affect white matter regions, at various ages and between males and females, and we hypothesised that this is secondary to physiological variation in white matter glia with region, age and sex. Using single nucleus RNA sequencing of healthy human post-mortem samples, we find marked glial heterogeneity with tissue region (primary motor cortex, cerebellum, cervical spinal cord), with tissue-specific cell populations of oligodendrocyte precursor cells and astrocytes, and a spinal cord-enriched oligodendrocyte type that appears human-specific. Spinal cord microglia but not astrocytes show a more activated phenotype compared to brain. These regional effects, with additional differentially expressed genes with age and sex in all glial lineages, help explain pathological patterns of disease – essential knowledge for therapeutic strategies.
Single-cell RNA sequencing (scRNA-seq) is a widely used method for identifying cell types and trajectories in biologically heterogeneous samples, but it is limited in its detection and quantification of lowly expressed genes. This results in missing important biological signals, such as the expression of key transcription factors (TFs) driving cellular differentiation. We show that targeted sequencing of ∼1000 TFs (scCapture-seq) in iPSC-derived neuronal cultures greatly improves the biological information garnered from scRNA-seq. Increased TF resolution enhanced cell type identification, developmental trajectories, and gene regulatory networks. This allowed us to resolve differences among neuronal populations, which were generated in two different laboratories using the same differentiation protocol. ScCapture-seq improved TF-gene regulatory network inference and thus identified divergent patterns of neurogenesis into either excitatory cortical neurons or inhibitory interneurons. Furthermore, scCapture-seq revealed a role for of retinoic acid signaling in the developmental divergence between these different neuronal populations. Our results show that TF targeting improves the characterization of human cellular models and allows identification of the essential differences between cellular populations, which would otherwise be missed in traditional scRNA-seq. scCapture-seq TF targeting represents a cost-effective enhancement of scRNA-seq, which could be broadly applied to improve scRNA-seq resolution.
Oligodendroglia interact with neurons to support their health and maintain the normal functioning of the central nervous system (CNS). Human oligodendroglia are a highly heterogeneous population characterised by distinct developmental origins and regional differences, as well as variation in cellular states, as evidenced by recent analysis at single-nuclei resolution. Increasingly, there is evidence to suggest that the highly heterogeneous nature of oligodendroglia might underpin their role in a range of CNS disorders, including those with neuropsychiatric symptoms. Understanding the role of oligodendroglial heterogeneity in this group of disorders might pave the way for novel approaches to identify biomarkers and develop treatments.
BackgroundHarmful alcohol use is a leading cause of premature death, and is associated with age-related disease. Ageing is highly variable between individuals, and may deviate from chronological ageing, suggesting that biomarkers of biological ageing (based on DNA methylation or brain structural measures) may be clinically relevant. Here, we investigated the relationships between alcohol phenotypes and both brain and DNA methylation age estimates.MethodsFirst, using data from UK Biobank and Generation Scotland, we tested the association between alcohol consumption (units/week) or hazardous use (AUDIT scores), and accelerated brain and epigenetic ageing in 20,258 and 8,051 individuals, respectively. Second, we used Mendelian randomization to test for a causal effect of alcohol consumption levels and alcohol use disorder (AUD) on biological ageing.ResultsAlcohol use showed a consistent positive association with higher predicted brain age (AUDIT-C: β=0.053, p=3.16×10−13; AUDIT-P: β=0.052, p=1.6×10−13; total AUDIT score: β=0.062, p=5.52×10−16; units/week: β=0.078, p=2.20×10−16), and DNA methylation GrimAge (Units/week: β=0.053, p=1.48×10− 7) and PhenoAge (Units/week: β=0.077, p=2.18×10−10). Mendelian randomization analyses revealed some evidence for a causal effect of AUD on accelerated brain ageing (β=0.272, p=0.044), and no evidence for a causal effect of alcohol consumption levels on accelerated biological ageing.ConclusionsWe provide consistent phenotypic evidence linking alcohol use with accelerated biological ageing. There is possible evidence for a causal effect of AUD on brain age, but not for any other alcohol-related trait on brain or epigenetic age acceleration. Future studies investigating the mechanisms associating alcohol use with accelerated biological ageing are warranted.
Huntington's disease (HD) is a severely debilitating, autosomal dominant neurodegenerative disease with a fatal outcome. There is accumulating evidence of a prominent role of glia in the pathology of HD, and we investigated this by conducting single nuclear RNA sequencing (snRNAseq) of human post mortem brain in four differentially affected regions; caudate nucleus, frontal cortex, hippocampus and cerebellum. Across 127,205 nuclei from people with HD, and age/sex matched controls, we found heterogeneity of glia which is altered in HD. We describe prominent changes in the abundance of certain subtypes of astrocytes, microglia, oligodendrocyte precursor cells and oligodendrocytes between HD and control samples, and these differences are widespread across brain regions. Furthermore, we highlight two possible mechanisms that characterise the glial contribution to disease pathology. Firstly, we show that upregulation of molecular chaperones represents a cross-glial signature in HD, which likely reflects an adaptive response to the accumulation of mutant Huntingtin (mHTT). Secondly, we show an oligodendrocyte-specific upregulation of the calmodulin-dependent 3',5'-cyclic nucleotide phosphodiesterase 1A (PDE1A) in HD brain compared to controls, which may cause dysfunction of key cellular functions due to the downregulation of the important second messengers cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP). Our results support the hypothesis that glia have an important role in the pathology of HD, and show that all types of glia are affected in the disease. As glia are more tractable to treat than neurons, our findings may be of therapeutic relevance.
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