The Tudor-domain protein TDRD7, mutated in congenital cataract, controls the heat shock protein HSPB1 (HSP27) and lens fiber cell morphology
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA554941 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR9695090_1.fastq.gz | Fastqsanger.gz | |||
| SRR9695090_2.fastq.gz | Fastqsanger.gz | |||
| SRR9695091_1.fastq.gz | Fastqsanger.gz | |||
| SRR9695091_2.fastq.gz | Fastqsanger.gz | |||
| SRR9695088_1.fastq.gz | Fastqsanger.gz |
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Project description:Mutations of the RNA-granule component TDRD7 (OMIM: 611258) cause pediatric cataract in humans. Here, we applied an integrated approach to elucidate the molecular pathology of cataract in Tdrd7 targeted-knockout (Tdrd7-/-) mice. Tdrd7-/- animals precipitously develop lens fiber cell abnormalities early in life, suggesting a global-level breakdown/mis-regulation of key cellular processes. High-throughput RNA-sequencing followed by iSyTE-integrated bioinformatics-based analysis identified the molecular chaperone and cytoskeletal-modulator, HSPB1 (HSP27), among the high-priority down-regulated candidates in Tdrd7-/- lens. Moreover, a protein 2-D fluorescence difference gel electrophoresis-coupled mass spectrometry screen also identified HSPB1 to be reduced in Tdrd7-/- lens, offering independent support for focusing efforts on this factor to explain Tdrd7-/- cataract. Reduction of HSPB1 preceded lens morphological abnormalities, suggesting that cytoskeletal defects underlie the Tdrd7-/- cataract phenotype. In agreement, scanning electron microscopy revealed abnormal fiber cell membrane protrusions in Tdrd7-/- lenses. Significantly, abnormal F-actin staining was detected specifically in Tdrd7-/- fiber cells that exhibit nuclear degradation, thereby revealing that there are distinct mechanisms based on pre- or post-nuclear degradation differentiation stage for F-actin cytoskeletal maintenance in fiber cells. Further, RNA-immunoprecipitation identified Hspb1 mRNA in wild-type lens lysate TDRD7-pulldowns, and single-molecule RNA-imaging showed co-localization of TDRD7 protein with cytoplasmic Hspb1 mRNA in a specific pre-nuclear degradation area of differentiating fiber cells, indicating that TDRD7-ribonucleoprotein complexes are necessary for controlling optimal levels of key factors in lens development. Together, these data uncover a novel role for TDRD7 in regulating elevation of stress-responsive chaperones for cytoskeletal maintenance in post-nuclear degradation lens fiber cells, perturbation of which causes early-onset cataracts.
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Project description:To analyze the role of HSP27 in bleomycin (BLM)-induced pulmonary fibrosis in vivo, we used TG mice that conventionally overexpressed HSP27. Our previously reported that HSP27 plays an important role in pulmonary fibrosis. In mice overexpressing HSPB1, BLM-induced fibrotic regions and collagen deposits were increased compared with those in control BL6 mice. Following intratracheal treatment of BLM, the HSP25 TG mice showed an abundance of mononuclear and neutrophils cells in the alveoli, greater destruction of alveolar septa, intra-alveolar hyaline membrane formation, and a marked increase in collagen deposition compared with control BL6 mice.
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Project description:Mutations/deficiency of TDRD7, which encodes a tudor domain containing protein involved in post-transcriptional gene expression control, causes early-onset cataract in humans and animal models. While Tdrd7 is implicated in the control of key lens mRNAs, the impact of Tdrd7 deficiency on microRNAs (miRNAs), and how this contributes to cataracts, is undefined. Here, we address this critical knowledge-gap by investigating Tdrd7-targeted knockout (Tdrd7-/-) mice that exhibit fully penetrant juvenile cataracts. To gain global insights into miRNA profile alterations, we performed Affymetrix miRNA 3.0 microarray analysis on Tdrd7-/- mouse lenses at postnatal day (P) 4, because this stage precedes cataract formation and thus informs on early miRNA misexpression while minimizing detection of secondary changes.
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Project description:Mutations of the RNA granule component TDRD7 (OMIM: 611258) cause pediatric cataract. We applied an integrated approach to uncover the molecular pathology of cataract in Tdrd7-/- mice. Early postnatal Tdrd7-/- animals precipitously develop cataract suggesting a global-level breakdown/misregulation of key cellular processes. High-throughput RNA sequencing integrated with iSyTE-bioinformatics analysis identified the molecular chaperone and cytoskeletal modulator, HSPB1, among high-priority downregulated candidates in Tdrd7-/- lens. A protein fluorescence two-dimensional difference in-gel electrophoresis (2D-DIGE)-coupled mass spectrometry screen also identified HSPB1 downregulation, offering independent support for its importance to Tdrd7-/- cataractogenesis. Lens fiber cells normally undergo nuclear degradation for transparency, posing a challenge: how is their cell morphology, also critical for transparency, controlled post-nuclear degradation? HSPB1 functions in cytoskeletal maintenance, and its reduction in Tdrd7-/- lens precedes cataract, suggesting cytoskeletal defects may contribute to Tdrd7-/- cataract. In agreement, scanning electron microscopy (SEM) revealed abnormal fiber cell morphology in Tdrd7-/- lenses. Further, abnormal phalloidin and wheat germ agglutinin (WGA) staining of Tdrd7-/- fiber cells, particularly those exhibiting nuclear degradation, reveals distinct regulatory mechanisms control F-actin cytoskeletal and/or membrane maintenance in post-organelle degradation maturation stage fiber cells. Indeed, RNA immunoprecipitation identified Hspb1 mRNA in wild-type lens lysate TDRD7-pulldowns, and single-molecule RNA imaging showed co-localization of TDRD7 protein with cytoplasmic Hspb1 mRNA in differentiating fiber cells, suggesting that TDRD7-ribonucleoprotein complexes may be involved in optimal buildup of key factors. Finally, Hspb1 knockdown in Xenopus causes eye/lens defects. Together, these data uncover TDRD7's novel upstream role in elevation of stress-responsive chaperones for cytoskeletal maintenance in post-nuclear degradation lens fiber cells, perturbation of which causes early-onset cataracts.
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Project description:human bronchial smooth muscle cells were infected with adenoviral constructs containing either the phosphorylation mutant form of HSP27 (HSP27-3A) or the wild type form (HSP27-WT) at 40 MOI for 4 days. All sets were stimulated with a cytokine mixture containing 10 ng/ml IL-1beta, TNF-alfa, and gamma-IFN for 20 hours prior to harvest. This series represents 4 separate preparations of cells and RNA, with each set being subjected to a dye flip and hybridized to 2 different slides. Keywords: parallel sample
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Project description:Ovarian cancer has the worst prognosis in major gynecological cancers. Current therapies includes platinum, taxol, angiogenesis inhibitor, PARP inhibitor. However, most ovarian cancer patients develop resistance. Identification of more pro-tumor factors in ovarian cancer may shed insight into ovarian cancer biology and therapy. In this study, we find ZKSCAN3, a zinc-finger transcription factor is overexpressed in ovarian cancer. We show ZKSCAN3 promotes ovarian cancer cell proliferation. Through RNA-sequencing and ChIP-sequencing, HSPB1 is identified as a target gene of ZKSCAN3. HSPB1 expression is significantly decreased by suppressing ZKSCAN3. Suppressing HSPB1 expression inhibits ovarian cancer cell proliferation as well. In contrast, expressing exogenous HSPB1 partially rescues the cell proliferation in ZKSCAN3 knock-down cells. Collectively, our study uncovers a functional ZKSCAN3-HSPB1 axis that promotes ovarian cancer cell proliferation.
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Project description:human bronchial smooth muscle cells were infected with adenoviral constructs containing either the phosphorylation mutant form of HSP27 (HSP27-3A) or the wild type form (HSP27-WT) at 40 MOI for 4 days. All sets were stimulated with a cytokine mixture containing 10 ng/ml IL-1beta, TNF-alfa, and gamma-IFN for 20 hours prior to harvest. This series represents 4 separate preparations of cells and RNA, with each set being subjected to a dye flip and hybridized to 2 different slides.
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Project description:Colorectal cancer (CRC) shows limited responsiveness to immune-checkpoint blockade, highlighting the need for further investigation. The intratumoral Treg/CD8⁺ T-cell ratio serves as a predictive biomarker for therapeutic efficacy. Here, we first demonstrate that targeting HSPB1 lowers this ratio and confers therapeutic benefit in CRC. Methods. Candidate genes were identified by integrative single-cell transcriptomics and spatial transcriptomics, followed by survival analyses of TCGA cohorts. Functional interrogation was performed using CRISPR-Cas9 engineered knockout cell lines. Subcutaneous tumor models were established, and the immune microenvironment was characterized by multiparametric flow cytometry. Mechanistic validation was achieved through bulk RNA-seq and complementary functional assays. Results. Single-cell profiling identified HSPB1 as a determinant of the intratumoral Treg/CD8⁺ T-cell ratio, and TCGA analysis showed its prognostic relevance in CRC. Spatial transcriptomics revealed colocalization of HSPB1-expressing tumor cells with Tregs. Subcutaneous tumor models demonstrated that CRISPR-mediated HSPB1 deletion or pharmacologic inhibition markedly suppressed tumor growth and reprogrammed the Treg-dominated microenvironment. In vitro polarization assays confirmed that targeting HSPB1 selectively restrains Treg differentiation without affecting Th17. Integrated transcriptomic and functional studies further elucidated that HSPB1 orchestrates CCL20–CCR6 mediated Treg recruitment, thereby shaping the immunosuppressive milieu within colorectal tumors.Conclusions. Targeting HSPB1 exerts dual anti-tumor effects by directly suppressing neoplastic proliferation and concurrently alleviating Treg-mediated immunosuppression within the tumor microenvironment.
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