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Transcriptional Program of Kpna2 (Importin-alpha2) Regulates Cellular Differentiation-Coupled Circadian Clock Development in Mammalian Cells

ABSTRACT: The circadian clock in mammalian cells is cell-autonomously generated during the cellular differentiation process, but the underlying mechanisms are not understood. Here we show that perturbation of transcriptional program by constitutive expression of c-Myc and Dnmt1 ablation disrupts the differentiation-coupled emergence of the clock from mouse embryonic stem cells (ESCs). Using these model ESCs, 484 genes are identified by global gene expression analysis as correlating factors with differentiation-coupled circadian clock development. Among them, we find the misregulation of Kpna2 (Importin-alpha2) during the differentiation of the c-Myc over-expressed and Dnmt1-/- ESCs, in which sustaining cytoplasmic accumulation of PER proteins is observed. Moreover, constitutive expression of Kpna2 during the differentiation culture of ESCs significantly impairs clock development and KPNA2 facilitates cytoplasmic localization of PER1/2. These results suggest that the programmed gene expression network regulates the differentiation-coupled circadian clock development in mammalian cells, at least in part via post-transcriptional regulation of clock proteins.

ORGANISM(S): Mus musculus

PROVIDER: GSE61184 | GEO | 2014/11/13

SECONDARY ACCESSION(S): PRJNA260445

REPOSITORIES: GEO

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Transcriptional Program of Kpna2 (Importin-α2) Regulates Cellular Differentiation-Coupled Circadian Clock Development in Mammalian Cells

Project description:The circadian clock in mammalian cells is cell-autonomously generated during the cellular differentiation process, but the underlying mechanisms are not understood. Here we show that perturbation of transcriptional program by constitutive expression of c-Myc and Dnmt1 ablation disrupts the differentiation-coupled emergence of the clock from mouse embryonic stem cells (ESCs). Using these model ESCs, 484 genes are identified by global gene expression analysis as factors correlated with differentiation-coupled circadian clock development. Among them, we find the misregulation of Kpna2 (Importin-α2) during the differentiation of the c-Myc over-expressed and Dnmt1-/- ESCs, in which sustained cytoplasmic accumulation of PER proteins is observed. Moreover, constitutive expression of Kpna2 during the differentiation culture of ESCs significantly impairs clock development and KPNA2 facilitates cytoplasmic localization of PER1/2. These results suggest that the programmed gene expression network regulates the differentiation-coupled circadian clock development in mammalian cells, at least in part via post-transcriptional regulation of clock proteins.

2014-11-13 | GSE61096 | GEO

Identification and quantification of KPNA2 phosphorylation and interactome in response to hydrogen peroxide-induced oxidative stress

Project description:Karyopherin α 2 (KPNA2, importin α1) is involved in the nuclear import of proteins and participates in cellular processes and accumulates in the nucleus under cellular stresses including hydrogen peroxide-indeced oxidative stress via unknown mechanisms. We performed the immunoprecipitation assay and SILAC-based quantitative proteomic analysis in HeLa cells to reveal that hydrogen peroxide decreased the phosphorylation of KPNA2 at serine 62 (S62) and increased its interaction with nucleophosmin 1 (NPM1). Specifically, a reduction in phosphorylated S62 on KPNA2 was observed in the cytoplasmic fraction, but this phosphorylated KPNA2 was not detected in the nuclear fraction. We also identified fifty-four KPNA2-interacting proteins in the nuclear fraction. Among them, NPM1, RPLP0, and MYH9 interacted with KPNA2 in cells exposed to hydrogen peroxide but not in unstressed control cells. Furthermore, the subcellular fractionation, immunoprecipitation, western blotting, immunofluorescence assay, and qRT-PCR analyses were used to support a novel finding that S62 phosphorylation maintains KPNA2 in the cytoplasm, and hydrogen peroxide reduces the phosphorylation of KPNA2 S62 to promote KPNA2-NPM1 complex nuclear entry for gene regulation.

2024-10-17 | PXD051121 | Pride

Mus musculus

Project description:Transcriptional Program of Kpna2 (Importin-alpha2) Regulates Cellular Differentiation-Coupled Circadian Clock Development in Mammalian Cells

| PRJNA260445 | ENA

Mus musculus

Project description:Transcriptional Program of Kpna2 (Importin-α2) Regulates Cellular Differentiation-Coupled Circadian Clock Development in Mammalian Cells

| PRJNA260215 | ENA

Development of human cartilage circadian rhythm in a stem cell-chondrogenesis model

Project description:The circadian clock in murine articular cartilage is a critical temporal regulatory mechanism for tissue homeostasis and osteoarthritis. However, translation of these findings into humans has been hampered by the difficulty in obtaining circadian time series human cartilage tissues. As such, a suitable model is needed to understand the initiation and regulation of circadian rhythms in human cartilage. We used a chondrogenic differentiation protocol on human embryonic stem cells (hESCs) as a proxy for early human chondrocyte development. Chondrogenesis was validated using histology and expression of pluripotency and differentiation markers. The molecular circadian clock was tracked in real time by lentiviral transduction of human clock gene luciferase reporters. Differentiation-coupled gene expression was assessed by RNAseq and differential expression analysis.

2022-08-16 | E-MTAB-11758 | biostudies-arrayexpress

RNA Binding protein KPNA2 promotes the progress of gastric cancer by regulating alternative splicing of related genes [RIP-seq]

Project description:RNA binding proteins (RBPs) took a critical part in genome regulation. kpna2, as an essential member of the RBP family, was found to be highly expressed and associated with lymph node metastasis in gastric cancer (GC). Transcriptional sequencing data were used to find that KPNA2 primarily regulated alternative 5' splice site (A5SS), alternative 3'splice site (A3SS), exon skipping (ES) and cassette exon. Vitally, KPNA2 was involved in the transcriptional regulation of cancer-related genes. Therefore, we screened potential targets in AGS cells with differential expression and alternative splicing (AS) levels regulated by KPNA2, further identifying that KPNA2 was engaged in biological processes concerning immune response, cell proliferation and apoptosis in GC through transcriptional regulation. Besides, the binding sites of KPNA2 to spliceosomes were identified using improved RNA immunoprecipitation sequencing techniques, and KPNA2 was preferentially bound to the intron region. Notably, KPNA2 regulated the A3SS AS mode of WDR62, which may increase the malignancy of GC. Finally, we also discovered that AS of immune-related molecules can be regulated by KPNA2. Overall, for the first time, our results demonstrated that KPNA2 served as an oncogenic splicing factor in GC regulating AS and differential expression of GC-related genes and may represent a potential target for GC therap

2024-08-02 | GSE201419 | GEO

RNA Binding protein KPNA2 promotes the progress of gastric cancer by regulating alternative splicing of related genes [RNA-seq]

2024-08-02 | GSE201418 | GEO

Disruption of circadian clockwork in in vivo reprogramming-induced mouse kidney tumors

Project description:The circadian clock, which regulates cellular physiology, such as energy metabolism, resides in each cell level throughout the body. Recently, it has been elucidated that the cellular circadian clock is closely linked with cellular differentiation. Moreover, the misregulation of cellular differentiation in mouse embryonic stem cells (ESCs) induced abnormally differentiated cells with impaired circadian clock oscillation, concomitant with the post-transcriptional suppression of CLOCK proteins. Here, we show that the circadian molecular oscillation is disrupted in dysdifferentiation-mediated mouse kidney tumors induced by partial in vivo reprogramming, resembling Wilms tumors. The expression of CLOCK protein was dramatically reduced in the tumor cells despite the Clock mRNA expression. We also showed that a similar loss of CLOCK was observed in human Wilms tumors, suggesting that the circadian molecular clockwork may be disrupted in dysdifferentiation-mediated embryonal tumors such as Wilms tumors, similar to the in vivo reprogramming induced mouse kidney tumors. These results support our previous reports and may provide a novel viewpoint for understanding the pathophysiological nature of cancers through the correlation between cellular differentiation and circadian clock.

2018-02-13 | GSE107261 | GEO

Identification of KPNA2 targets by RNA-Seq in osteosarcoma

Project description:Despite recent advances, the poor outcomes in osteosarcoma suggest that novel therapeutic targets are needed. Karyopherin alpha 2 (KPNA2) is a nuclear import factor, which functions as an oncogene in many cancers. However, the role of KPNA2 in osteosarcoma and its mechanism of action are still unclear. To identify gene signatures that play a role in metastasis, we performed RNA-Seq of gene expression profiling on U2OS cells treated with siKPNA2 and siNC (in triplicate for each group).

2023-06-16 | GSE206342 | GEO

Loss of the importin Kpna2 causes infertility in male maice by disrupting the translocation of testis-specific transcription factors

Project description:Karyopherin proteins mediate the movement between the nucleus and cytoplasm of specific proteins that are essential for spermatogenesis. Through a loss-of-function approach, we here examine the specific role of Karyopherin Subunit Alpha 2 (Kpna2) in spermatogenesis and male fertility. The factors determined were (i) the spatial distribution of KPNA2 in the testis using immunofluorescence; (ii) the morphological and functional consequences of Kpna2 deficiency in terms of sperm production, quality, and motility, and fertility in knock-out and wild-type mice; and (iii) the transcriptomic consequences of Kpna2 deficiency in knock-out compared to wild-type mice by RNA-seq analysis. KPNA2 was found expressed in the cytoplasm of primary spermatocytes and the nucleus and cytoplasm of secondary spermatocytes and spermatid cells. Ablation of Kpna2 in male mice reduced their size, affected sperm motility, increased sperm abnormalities, and led to dysregulation of testis gene expression and ultimately to infertility. Impaired mRNA expression mainly affected clusters of genes expressed in spermatids and spermatocytes. Downregulated genes include a set of genes that participate in cell adhesion, extracellular matrix (ECM) organization, and ECM-receptor interaction. We detected the enrichment of some transcription factors that bind to regions around transcription start sites of downregulated genes. We propose an essential role of Kpna2 in spermatogenesis via the disrupted translocation of testis specific transcription factors that control the expression of genes related to ECM organization in the seminiferous tubules.

2023-07-19 | GSE213442 | GEO

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