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Aberrant splicing in Huntington’s disease accompanies disrupted TDP-43 activity and altered m6A RNA modifications [eCLIP-seq]

ABSTRACT: Aberrant splicing in Huntington’s disease accompanies disrupted TDP-43 activity and altered m6A RNA modifications [eCLIP-seq]

PROVIDER: PRJNA1169368 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR30893900_1.fastq.gz	Fastqsanger.gz
	SRR30893900_2.fastq.gz	Fastqsanger.gz
	SRR30894000_1.fastq.gz	Fastqsanger.gz
	SRR30894000_2.fastq.gz	Fastqsanger.gz
	SRR30893901_1.fastq.gz	Fastqsanger.gz

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Aberrant splicing in Huntington’s disease accompanies disrupted TDP-43 activity and altered m6A RNA modifications [eCLIP-seq]

Project description:Huntington’s disease (HD) is a neurodegenerative disorder caused by a CAG repeat expansion in the first exon of the HTT gene, leading to altered gene expression. However, the mechanisms leading to disrupted RNA processing in HD remain unclear. Here, we identify the RNA-binding TDP-43 and the N6-methyladenosine (m6A) writer protein METTL3 to be upstream regulators of exon skipping in multiple HD systems. Dysregulated nuclear localization of TDP-43 and cytoplasmic accumulation of phosphorylated TDP-43 is shown to be present in HD mice and human brains with TDP-43 co-localizing with HTT nuclear aggregate-like bodies distinct from mutant HTT inclusions and from previously observed TDP-43 pathologies. The binding of TDP-43 onto RNAs encoding HD-associated differentially expressed and aberrantly spliced genes is decreased. Finally, m6A RNA modification is reduced on RNAs abnormally expressed in the striatum from HD R6/2 mouse brain, including at clustered sites adjacent to TDP-43 binding sites. Our evidence supports TDP-43 loss of function coupled with altered m6A modification as a mechanism underlying alternative splicing in HD and highlights the critical nature of TDP-43 loss of function across multiple neurodegenerative diseases.

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Aberrant splicing in Huntington’s disease accompanies disrupted TDP-43 activity and altered m6A RNA modifications

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Aberrant splicing in Huntington’s disease accompanies disrupted TDP-43 activity and altered m6A RNA modifications [RASL-seq]

Project description:Aberrant splicing in Huntington’s disease accompanies disrupted TDP-43 activity and altered m6A RNA modifications [RASL-seq]

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5-ethynyluridine perturbs nuclear RNA metabolism to promote the nuclear accumulation of TDP-43 and other RNA binding proteins

Project description:TDP-43, an essential nucleic acid binding protein and splicing regulator, is disrupted in neurodegeneration and an urgent therapeutic target. We and others demonstrated that TDP-43 nuclear localization and function depend on the abundance of its nuclear pre-mRNA binding partners and its recruitment into large ribonucleoprotein complexes, which restricts TDP-43 nuclear efflux and maintains the critical nuclear pool of TDP-43. To further investigate the interplay between TDP-43 and nascent RNAs, we set out to employ 5-ethynyluridine (5EU), a widely used uridine analog that enables ‘click chemistry’ labeling of nascent RNAs. Unexpectedly, 5EU induced the nuclear accumulation of TDP-43 and other nuclear RNA binding proteins (RBPs) and attenuated TDP-43 nuclear exit. RNA FISH demonstrated 5EU-induced nuclear accumulation of polyadenylated and GU-rich RNAs. TDP-43 eCLIP confirmed that 5EU stabilizes TDP-43 binding to intronic sites, and TDP-43 function in cryptic exon repression remained intact. There was no major change in RNA stability, but RNA-seq demonstrated a marked alteration in RNA splicing, which is less efficient in 5EU-treated cells. Thus, 5EU perturbs nuclear RNA metabolism leading to nuclear RNA and RBP accumulation. These findings have critical implications for studies utilizing 5EU and identify a novel mechanistic inroad to support TDP-43 homeostasis.

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