Proliferative arrest induces neuron differentiation and innate immune responses in control and infectious CJD rat septal neurons
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ABSTRACT:
PROVIDER: PRJNA1137358 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR29881368_1.fastq.gz | Fastqsanger.gz | |||
| SRR29881368_2.fastq.gz | Fastqsanger.gz | |||
| SRR29881369_1.fastq.gz | Fastqsanger.gz | |||
| SRR29881369_2.fastq.gz | Fastqsanger.gz | |||
| SRR29881370_1.fastq.gz | Fastqsanger.gz |
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Project description:Rat postmitotic septal neurons (SEP) engineered to conditionally proliferate at 33oC were arrested at 37.5oC for weeks without cytotoxic effects. Nine independent cDNA libraries were interrogated to broadly evaluate elevations in b-interferon (b-IFN) and prion protein (PrP) found previously by RT/qPCR in arrested uninfected and CJD infected cells. RNA-seq revealed a variety of upregulated innate immune responses in control and CJD infected cells. Proliferating uninfected, and latently infected (CJ-) cells, showed rare RNA-seq differences. However, major quantitative changes became evident post-arrest. In uninfected cells these included anti-proliferative DNA replication/cell xxNeuregulin-1, GDF6, SFRP4 and PrP. Recruitment of many IFN innate immune pathways, complement, cytokines and clusterin were present in both sets but re-arrested cells with high infectivity (CJ+) escaped replication controls and suppressed neuronal differentiation. Moreover, IFN anti-viral stimulated networks (OAS, cytokines, IFN- and metalloproteinases) were also enhanced among the 342 unique CJ+ transcripts, e.g., Il17, ISG15, CXCL10 and RSAD2 (viperin). These data show 1) defensive innate immune molecules and/or pathways are produced by neurons and participate in normal neuronal differentiation; 2) CJD infectious agents that survive in an undetectable latent state can epigenetically prime cells to produce a strong anti-viral response; 3) downregulation of a plethora of proliferative pathways is also imprinted in cells exposed to infection. Several innate-immune transcripts shared with CJ+ myeloid microglia from brain may be physiologically stimulated to identify latent CJD infections that can be clinically silent for >30 years.
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Project description:Finite replicative potential is a defining feature of non-transformed somatic cells, first established by Leonard Hayflick in vitro using WI-38 human lung fibroblasts. Once proliferative capacity is exhausted due to telomere shortening, cells enter into a state called replicative senescence, which can be avoided through ectopic expression of telomerase reverse transcriptase (hTERT). As WI-38 cells approach replicative arrest, molecular pathways linked to mechanotransduction are induced, including YAP signaling, but the potential interplay between replicative lifespan and the mechanical environment of the cell remains unexplored. Here, we investigate the influence of mechanosensation on the trajectory towards replicative arrest taken by WI-38 cells by growing cells on substrates of varying stiffnesses. Matrix softening slowed proliferation, altered cellular phenotypes, and shortened proliferative lifespan while hTERT expression abrogated or reduced these responses. Our analyses of bulk and single-cell RNA-sequencing and ATAC-sequencing revealed the emergence of a unique G1 transcriptional state on soft substrates, characterized by an AP-1 transcription factor program, which failed to manifest with hTERT expression. Together, these findings reveal how the mechanical environment alters WI-38 cell proliferative lifespan and dictates unique paths towards growth arrest.
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