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5-hydroxymethylcytosine is Dynamically Regulated During Forebrain Organoid Development and Prematurely Altered in Forebrain Organoids of Alzheimer’s Disease Patients

ABSTRACT: 5-hydroxymethylcytosine is Dynamically Regulated During Forebrain Organoid Development and Prematurely Altered in Forebrain Organoids of Alzheimer’s Disease Patients

PROVIDER: PRJNA637330 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR11926708_1.fastq.gz	Fastqsanger.gz
	SRR11926708_2.fastq.gz	Fastqsanger.gz
	SRR11926709_1.fastq.gz	Fastqsanger.gz
	SRR11926709_2.fastq.gz	Fastqsanger.gz
	SRR11926710_1.fastq.gz	Fastqsanger.gz

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5-hydroxymethylcytosine is Dynamically Regulated During Forebrain Organoid Development and Prematurely Altered in Forebrain Organoids of Alzheimer’s Disease Patients

Project description:5-hydroxymethylcytosine (5hmC) endures dynamic changes during mammalian brain development and its aberrant regulation is known to be associated with numerous neurological diseases such as Alzheimer’s Disease (AD). Recent evidence suggests that key epigenetic changes could occur during neural development long before the onset of neurodegenerative disorders. However, the dynamics of 5hmC during early human brain development and how that contributes to pathogenesis of neurodegeneration, particularly AD pathologies, remain largely unexplored. To investigate this, we utilized the human iPSC-derived organoid model. We derived the 5hmC and transcriptome profiles across healthy forebrain-organoid developmental time points, as well as a patient derived AD organoid time point, allowing us to study brain development at the cellular and molecular levels. In the present study, we identified stage specific differentially hydroxymethylated regions that demonstrated unique acquisition and depletion of 5hmC modifications across development stages. In addition, genes bearing concomitant increases or decreases in both 5hmC and gene expression were enriched in neurobiological processes or early developmental processes respectively. Our AD organoids corroborate both cellular and epigenetic phenotypes previously observed in human AD brains. Importantly, in AD organoids, we identified significant 5hmC alterations at key neurodevelopmental and AD-risk genes, consequently downregulating genes involved in neurodevelopmental and immune response pathways. Collectively our data indicates that, during human fetal neurodevelopment, the precise temporal regulation of 5hmC could modulate key gene expression patterns ensuring that critical neurodevelopmental milestones are achieved. Further, we also demonstrate that premature epigenetic dysregulation of the 5hmC landscape during neuronal development may predispose AD pathogenesis.

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5-hydroxymethylcytosine is dynamically regulated during forebrain organoid development and aberrantly altered in Alzheimer's disease.

Project description:5-hydroxymethylcytosine (5hmC) undergoes dynamic changes during mammalian brain development, and its dysregulation is associated with Alzheimer's disease (AD). The dynamics of 5hmC during early human brain development and how they contribute to AD pathologies remain largely unexplored. We generate 5hmC and transcriptome profiles encompassing several developmental time points of healthy forebrain organoids and organoids derived from several familial AD patients. Stage-specific differentially hydroxymethylated regions demonstrate an acquisition or depletion of 5hmC modifications across developmental stages. Additionally, genes concomitantly increasing or decreasing in 5hmC and gene expression are enriched in neurobiological or early developmental processes, respectively. Importantly, our AD organoids corroborate cellular and molecular phenotypes previously observed in human AD brains. 5hmC is significantly altered in developmentally programmed 5hmC intragenic regions in defined fetal histone marks and enhancers in AD organoids. These data suggest a highly coordinated molecular system that may be dysregulated in these early developing AD organoids.

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Project description:DNA 5-hydroxymethylcytosine (5hmC), also known as the sixth DNA base of the genome, plays an important role in neurogenerative disorders. However, little is known about its genome-wide distribution and its association with Alzheimer’s disease neuropathology. Here, we report a genome-wide profiling of 5hmC in 1,050 autopsied brains (dorsolateral prefrontal cortex) of older adults in the Religious Orders Study/Memory and Aging Project (ROSMAP) cohorts. This resource will facilitate future research of DNA methylation and demethylation in Alzheimer’s disease and other neurological disorders.

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Differential 5-methylcytosine and 5-hydroxymethylcytosine in Parkinson’s and Alzheimer’s Disease.

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Genomic instability in the naturally and prematurely aged myocardium

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Genome-wide gene expression profiling post PCCB knockdown in human forebrain organoids

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5-hydroxymethylcytosine-mediated epigenetic dynamics during neurodevelopment and aging [mRNA profiling]

Project description:DNA methylation dynamics influence brain function and are altered in neurological disorders. 5-hydroxymethylcytosine (5-hmC), a DNA base derived from 5-methylcytosine (5mC) accounts for ~40% of modified cytosine in brain, and has been implicated in DNA methylation-related plasticity. Here we map 5-hmC genome-wide across three ages in mouse hippocampus and cerebellum, allowing assessment of its stability and dynamic regulation during postnatal neurodevelopment through adulthood. We find developmentally programmed acquisition of 5-hmC in neuronal cells. Epigenomic localization of 5-hmC-regulated regions reveals stable and dynamically modified loci during neurodevelopment and aging. By profiling 5-hmC in human cerebellum we establish conserved genomic features of 5-hmC. Finally, we implicate 5-hmC in neurodevelopmental disease by finding that its levels are inversely correlated with methyl-CpG-binding protein 2 (Mecp2) dosage, a protein encoded by a gene in which mutations cause Rett Syndrome. These data point toward critical roles for 5-hmC-mediated epigenetic modification in neurodevelopment and diseases. Gene expression data derived from P7 and 6wk mouse cerebellum used for determining expression outcomes associated with dynamic alterations in 5-hydroxymethylcytosine

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