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Increased intron retention is a post-transcriptional signature associated with progressive ageing and Alzheimer’s disease

ABSTRACT: Increased intron retention is a post-transcriptional signature associated with progressive ageing and Alzheimer’s disease

PROVIDER: PRJNA433513 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR6689460_1.fastq.gz	Fastqsanger.gz
	SRR6689460_2.fastq.gz	Fastqsanger.gz
	SRR6689461_1.fastq.gz	Fastqsanger.gz
	SRR6689461_2.fastq.gz	Fastqsanger.gz
	SRR6689452_1.fastq.gz	Fastqsanger.gz

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Increased intron retention is a post-transcriptional signature associated with progressive ageing and Alzheimer’s disease

Project description:Intron retention (IR) may affect gene expression and protein functions during development and age-onset diseases. However, it remains unclear if IR undergoes spatial or temporal changes during different stages of ageing or neurodegenerative disorders like Alzheimer’s disease (AD). By profiling mRNA species across different ages of Drosophila heads, we observed significant increase in the level of IR of many conserved genes as animals aged. Interestingly, distinct sets of genes are affected at different stages of adult fly life with IR occurring at several AD-associated genes in old adult. This suggests that alteration of proper protein functions by IR during ageing may lead to AD pathogenesis. Consistent with this notion, analyses of healthy human ageing brains and different AD datasets revealed similar increased aberrant IR activities in many AD-curated genes. Taken together, our data suggest that increase IR during ageing may be the driver for late-onset sporadic AD.

2020-02-19 | GSE110349 | GEO

Intron retention analysis using isogrowth profiling

Project description:Intron retention analysis using isogrowth profiling

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Intron retention analysis using isogrowth profiling

Project description:We present an analysis of intron retention under stress from two different drugs and their combinations in yeast Saccharomyces cerevisiae. We previously established isogrowth profiling, a method to abstract the non-specific effects of growth rate inhibition from the specific effect of perturbation by a small molecule: two drugs are used at varied ratios, but at fixed overall growth inhibition. Here, cycloheximide and LiCl were used at seven different ratios along the 50% growth inhibition isobole and the total ribodepleted RNA was sequenced. This allowed us to gauge the changes in intron retention due to the used drugs, while ensuring that the effects are not caused by growth inhibition. We found a prominent increase in intron retention under LiCl treatment that preferentially affects introns contained in the transcripts of ribosomal proteins.

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Dynamic intron retention modulates gene expression in the monocytic differentiation pathway

Project description:We determined the role of intron retention in murine monocyte differentiation

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Towards resolution of the intron retention paradox in breast cancer

Project description:We explored intron retention patterns in normal breast epithelial cells (MCF10A) and estrogen receptor positive (ER+) breast cancer cells (MCF7).

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Stress-induced transcriptional readthrough into neighboring genes is linked to intron retention

Project description:Exposure to certain stresses leads to readthrough transcription downstream of gene ends. Here we found that this phenomenon impacts the expression of genes located downstream to readthrough genes, whereby readthrough transcription proceeds into downstream genes, termed read-in genes. Using polyA-selected RNA-seq data from mouse fibroblasts, we identified widespread read-in in heat shock, oxidative and osmotic stress conditions. Read-in genes share distinctive genomic characteristics; they are extremely short, mainly due to less, shorter, introns, and they are highly GC rich. Furthermore, using ribosome footprint profiling we found that the translation of genes with high degrees of read-in is significantly reduced. Strikingly, read-in genes show extremely high levels of intron retention during stress, mostly in their first intron. While read-in genes share features that are generally associated with increased likelihood of intron retention, such as short introns and high GC content, intron retention in read-in genes during stress exceeds greatly beyond what is expected given their genomic properties. Finally, we found that first introns in read-in genes have weaker 5’ and 3’ splice sites. Our data portray a relationship between read-in and intron retention, suggesting it may have co-evolved to facilitate reduced translation of read-in genes during stress.

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Progressive Senescence Programs Elicit Intrinsic Vulnerability to Ageing-related Cancer

Project description:Cancer incidence escalates exponentially with advancing age, the mechanism of which remains obscure. Here we built up a chronological molecular clock at the single cell level for the mammary stem cell enriched population to depict the physiological ageing dynamics. We found the mammary ageing process was asynchronous and progressive, determined by the relative proportions of four distinct cellular states. The mammary ageing was initiated by a light senescence state with elevated NFkb, P53 signals, followed by a deep senescence state with reduced NFkb, P53 and enhanced PI3K-Akt-mTOR, Wnt, Notch and pluripotency activities succumb to cancer predisposition. Both of these senescence programs were regulated by a master mammary stem cell factor Bcl11b through modulation of multiple stress, longevity and pluripotency associated pathways. Depletion of Bcl11b triggered morphological, functional and molecular ageing-like phenotypes, and drastically enhanced DMBA-induced tumor formation. We further screened out a drug TPCA-1 that can elevate Bcl11b activity, rejuvenate mammary cells transcriptomically and significantly reduce the ageing-related cancer incidence. Our findings established a molecular portrait of progressive mammary cell ageing and elucidated the regulatory network bridging mammary ageing and cancer predisposition that can be modulated to control the cancer initiation, which has potential implications in management of cancer prevalence.

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Project description:ZCRB1 is a RNA binding protein involved in the Minor Spliceosome. Here, we used shRNAs to knock down ZCRB1 in HCT116 cells to analysis the function of ZCRB1 in gene expression and intron retention.

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Project description:15.5K is a RNA binding protein involved in the Minor Spliceosome. Here, we used shRNAs to knock down 15.5K in HEK293T cells to analysis the function of 15.5K in gene expression and intron retention.

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Reactive astrocytes in ALS models display dysregulated intron retention

Project description:Reactive astrocytes in ALS models display dysregulated intron retention

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