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RNA-seq of control and TIA1-knockdown HMC3 cells

ABSTRACT: The study aims to utilize RNA-seq to characterize the transcriptomic alterations in TIA1-knockdown HMC3 cells compared to control cells, with the goal of identifying differentially expressed genes and elucidating the molecular pathways and biological processes regulated by TIA1, a key RNA-binding protein. By profiling gene expression changes following TIA1 depletion, the research seeks to uncover how this protein influences cellular functions in HMC3 cells, a model of human microglia critical for central nervous system immunity and homeostasis. Given the established role of TIA1 in mRNA metabolism and its links to neurodegenerative disorders like amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), this study holds relevance for understanding microglial gene regulatory mechanisms disrupted in disease contexts. Identifying TIA1-dependent transcriptomic signatures in HMC3 cells can provide insights into the functional consequences of TIA1 dysfunction in microglia, potentially revealing novel therapeutic targets or biomarkers for neurological diseases while advancing our understanding of RNA-mediated regulatory networks in immune cells of the brain.

ORGANISM(S): Homo sapiens

PROVIDER: GSE297158 | GEO | 2025/05/24

REPOSITORIES: GEO

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Project description:During cell stress, the transcription and translation of immediate early genes are prioritized, while most other mRNAs are stored away in stress granules or degraded in P-bodies. TIA-1 is an mRNA binding protein that needs to translocate from the nucleus to seed the formation of stress granules in the cytoplasm. Since other stress granule components such as TDP-43, FUS, ATXN2, SMN, MAPT, HNRNPA2B1 and HNRNPA1 are crucial for the motor neuron diseases ALS / SMA and for the frontotemporal dementia FTD, here we studied mouse nervous tissue to identify mRNAs with selective dependence on Tia1 deletion. Transcriptome profiling with oligonucleotide microarrays in comparison of spinal cord and cerebellum, together with independent validation in quantitative reverse transcriptase PCR and immunoblots demonstrated several strong and consistent dysregulations. In agreement with previously reported TIA1 knock-down effects, cell cycle and apoptosis regulators were affected markedly with expression changes up to 2-fold, exhibiting increased levels for Cdkn1a, Ccnf, and Tprkb versus decreased levels for Bid and Inca1 transcripts. Novel and surprisingly strong expression alterations were detected for fat storage and membrane trafficking factors, with prominent above 3-fold upregulations of Plin4, Wdfy1, Tbc1d24, and Pnpla2, versus a 0.5 -fold?? downregulation of Cntn4 transcript, encoding an axonal membrane adhesion factor with established haploinsufficiency. In comparison subtle effects on the RNA processing machinery included up to 1.2-fold upregulations of Dcp1b and Tial1. The effect on lipid dynamics factors is noteworthy, since also the gene deletion of Tardbp (encoding TDP-43) and Atxn2 led to fat metabolism phenotypes in mouse. In conclusion, genetic ablation of the stress granule nucleator TIA-1 has a novel major effect on mRNAs encoding lipid homeostasis factors in the brain. Factorial design comparing Tia1 knock-out mice with wild type littermates in four different tissues (midbrain, cerebellum, liver, spinal cord) and 2 different ages.

Project description:T-cell intracellular antigen-1 (TIA1) is an RNA-binding protein modulating many regulatory aspects of target mRNA metabolism. Despite several reports referring to the role of TIA1 in carcinogenesis, little is known about the significance of its expression and function in human cancers including esophageal squamous cell carcinoma (ESCC). In the present study, we found that ectopic localization of overexpressed TIA1 in the cytoplasm was observed in a cohort of 143 ESCC patients using immunohistochemistry, and the cytoplasmic TIA1 was an independent prognosticator for worse overall survival. Moreover, we revealed that TIA1 was overexpression in many ESCC cell lines, and silencing of TIA1 in those cells inhibited cell growth with an accumulation of cells in G0âG1 and sub-G1 phases. The human TIA1 gene generates two major protein isoforms, TIA1a and TIA1b. Expression of TIA1a isoform tended to be higher than that of TIA1b in ESCC cells, and TIA1a was expressed both in the nucleus and cytoplasm but TIA1b was expressed mainly in the nucleus. Further studies revealed that each isoform showed opposite effects on cell proliferation through ectopically introducing each gene: TIA1a promotes anchorage-dependent and independent cell proliferation, whereas TIA1b inhibits cell proliferation and/or induces cell death. The ribonucleoprotein immunoprecipitation followed by a microarray analysis or massive-parallel sequencing identified a set of TIA1-associating mRNAs including enriched cell cycle-associated genes. Among them, SKP2 and CCNA2 mRNA were shown to be interacted with TIA1 protein through their different regions, and SKP2 and CCNA2 protein levels were positively regulated by TIA1 through suppression of mRNA decay and translational induction, respectively. These findings provide new insights into the previously unknown role of TIA1 and its isoforms as tumor-promoting molecules regulating a set of downstream oncogenic proteins, and implicate their potential application as a useful marker of malignant potential and a therapeutic target in ESCC. To investigate the target molecules regulated by TIA1 in esophageal squamous cell carcinoma cell line (KYSE180), the expression levels of mRNAs (total) and transcripts captured by RIP with TIA1 antibody (TIA1_RIP) were analyzed using microarray.

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RNA-seq of control and TIA1-knockdown HMC3 cells

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