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Gene expression profiling in neuronal cells identifies a different type of transcriptome modulated by NF-Y [YAYC_Affymetrix]

ABSTRACT: We knocked down NF-Y in two types of neuronal cells, neuro2a neuroblastoma cells and sorted brain striatal cells, and performed gene expression profiling. We found that the down-regulated genes preferentially contained NF-Y-binding motifs in their proximal promoters, and notably enriched genes related to ER functions rather than those for cell cycle. These are highly contrast to the profiling data of HeLa and embryonic stem cells in which distinct down-regulation of cell cycle-related genes was observed by NF-Y knockdown. Clustering analysis further identified several functional clusters where populations of the down-regulated genes were highly distinct. Further analyses using chromatin immunoprecipitation and RNA-seq data revealed that transcriptomic difference was not correlated with the DNA binding of NF-Y but with splicing of NF-YA. These data suggest that neuronal cells have a different type of transcriptome in which ER-related genes are dominantly modulated by NF-Y, and imply that NF-YA splicing alteration rather than DNA-binding preference could be involved in this cell type-specific gene modulation.

ORGANISM(S): Mus musculus

PROVIDER: GSE151145 | GEO | 2020/12/16

REPOSITORIES: GEO

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Project description:Background: Approaches based on expression signatures of prostate cancer (PCa) have been proposed to predict patients’ outcomes and response to treatments. The transcription factor NF-Y participates to the progression from benign epithelium to both localized and metastatic PCa and is associated with aggressive transcriptional profile. The gene encoding for NF-YA, the DNA-binding subunit of NF-Y, produces two alternatively spliced transcripts, NF-YAs and NF-YAl. Bioinformatic analyses pointed at NF-YA splicing as a key transcriptional signature to discriminate between different tumor molecular subtypes. In this study, we aimed to determine the pathophysiological role of NF-YA splice variants in PCa and their association with aggressive PCa subtypes. Methods: Data on the expression of NF-YA isoforms were extracted from the TCGA (The Cancer Genome Atlas) database of tumor prostate tissues and validated in prostate cell lines. Through lentiviral transduction and CRISPR-Cas9 technology, we modulated the expression of NF-YA splice variants in prostate cancer cells. We investigated cellular and molecular effects on cancer programs through 2D/3D in vitro assays and RNA-seq profilings. The rank-rank hypergeometric overlap approach (RRHO) was used to identify concordant/discordant overlap between gene expression signatures of NF-YAs/NF-YAl cells and human PCa patients. We performed in vivo studies in SHO-SCID mice to determine pathological and molecular phenotypes of NF-YAs/NF-YAl xenograft tumors. Results: NF-YA depletion affects the tumorigenic potential of prostate cancer cells in vitro and in vivo. Elevated NF-YAs levels are associated to aggressive prostate cancer specimens, defined by Gleason Score and TNM classification. NF-YAl overexpression in prostate cancer cells increases cell motility, while NF-YAs enhances both cell proliferation and invasive properties in 3D cultured spheroids and xenograft tumors. NF-YAs-transcriptome of multi-cellular spheroids has an extensive overlap with both localized and metastatic human PCa signatures. The ratio between NF-YAs and NF-YAl transcripts is higher in LumB PAM50 subtype, characterized by poor prognosis, and stratification of patients based on NF-YAs expression is predictive of clinical outcome. Conclusions: Altogether, our results indicate that the modulation of NF-YA isoforms affects prostate pathophysiological processes and contributes to cancer-relevant phenotype, in vitro and in vivo. Evaluation of NF-YA splicing may represent a new molecular strategy for risk assessment of PCa patients.

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Gene expression profiling in neuronal cells identifies a different type of transcriptome modulated by NF-Y [YAYC_Affymetrix]

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