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Downregulation of m6A methyltransferase in the hippocampus of Tyrobp-/- mice and implications for learning and memory deficits

ABSTRACT: Downregulation of m6A methyltransferase in the hippocampus of Tyrobp-/- mice and implications for learning and memory deficits

PROVIDER: PRJNA745190 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR15089700.fastq.gz	Fastqsanger.gz
	SRR15089701.fastq.gz	Fastqsanger.gz
	SRR15089702.fastq.gz	Fastqsanger.gz
	SRR15089679.fastq.gz	Fastqsanger.gz
	SRR15089680.fastq.gz	Fastqsanger.gz

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Downregulation of m6A methyltransferase in the hippocampus of Tyrobp-/- mice and implications for learning and memory deficits

Project description:Loss-of-function mutations in the gene that encodes TYRO protein kinase-binding protein (TYROBP) cause Nasu-Hakola disease, a heritable disease resembling Alzheimer's disease (AD). Methylation of N6 methyl-adenosine (m6A) in mRNA plays essential roles in learning and memory. Aberrant m6A methylation has been detected in AD patients and animal models. In the present study, Tyrobp−/− mice showed learning and memory deficits in the Morris water maze, which worsened with age. Tyrobp−/− mice also showed elevated levels of total tau, Ser202/Thr205-phosphorylated tau and amyloid β in the hippocampus and cerebrocortex, which worsened with aging. The m6A methyltransferase components METTL3, METTL14, and WTAP were downregulated in Tyrobp−/− mice, while expression of demethylases that remove the m6A modification (e.g., FTO and ALKBH5) were unaltered. Methylated RNA immunoprecipitation sequencing identified 498 m6A peaks that were upregulated in Tyrobp−/− mice, and 312 m6A peaks that were downregulated. Bioinformatic analysis suggested that most of these m6A peaks occur in sequences near stop codons and 3′-untranslated regions. These findings suggest an association between m6A RNA methylation and pathological TYROBP deficiency.

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Downregulation of m6A Methyltransferase in the Hippocampus of <i>Tyrobp</i> <sup>-/-</sup> Mice and Implications for Learning and Memory Deficits.

Project description:Loss-of-function mutations in the gene that encodes TYRO protein kinase-binding protein (TYROBP) cause Nasu-Hakola disease, a heritable disease resembling Alzheimer's disease (AD). Methylation of N6 methyl-adenosine (m6A) in mRNA plays essential roles in learning and memory. Aberrant m6A methylation has been detected in AD patients and animal models. In the present study, Tyrobp-/- mice showed learning and memory deficits in the Morris water maze, which worsened with age. Tyrobp-/- mice also showed elevated levels of total tau, Ser202/Thr205-phosphorylated tau and amyloid β in the hippocampus and cerebrocortex, which worsened with aging. The m6A methyltransferase components METTL3, METTL14, and WTAP were downregulated in Tyrobp-/- mice, while expression of demethylases that remove the m6A modification (e.g., FTO and ALKBH5) were unaltered. Methylated RNA immunoprecipitation sequencing identified 498 m6A peaks that were upregulated in Tyrobp-/- mice, and 312 m6A peaks that were downregulated. Bioinformatic analysis suggested that most of these m6A peaks occur in sequences near stop codons and 3'-untranslated regions. These findings suggest an association between m6A RNA methylation and pathological TYROBP deficiency.

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A Missense Mutation in Kcnc3 Causes Hippocampal Learning Deficits in Mice

Project description:Although a wide variety of genetic tools have been developed to study learning and memory, the molecular basis of memory encoding remains incompletely understood. Here, we undertook an unbiased approach to identify novel genes critical for memory encoding. From a large-scale in vivo mutagenesis screen using contextual fear conditioning, we isolated a mutant, named Clueless, with spatial learning deficits. A causative missense mutation (G434V) was found in the voltage gated potassium channel, subfamily C member 3 (Kcnc3) gene in a region that encodes a transmembrane voltage sensor. Generation of a Kcnc3G434V CRISPR mutant mouse confirmed this mutation as the cause of the learning defects. While G434V had no effect on transcription, translation, or trafficking of the channel, electrophysiological analysis of the G434V Kcnc3 mutant channel revealed a complete loss of voltage-gated conductance, a broadening of the action potential, and decreased neuronal firing. Together, our findings have revealed a previously unrecognized role for Kcnc3 in learning and memory.

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ChIP-seq of CTCF from mouse hippocampus

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Partial loss of CFIm25 causes aberrant alternative polyadenylation and learning deficits [superseries]

Project description:Partial loss of CFIm25 causes aberrant alternative polyadenylation and learning deficits [superseries]

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