TDP-43 condensates and lipid droplets regulate the reactivity of microglia and regeneration after traumatic brain injury
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ABSTRACT:
PROVIDER: PRJNA742394 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR14993661.fastq.gz | Fastqsanger.gz | |||
| SRR14993662.fastq.gz | Fastqsanger.gz | |||
| SRR14993663.fastq.gz | Fastqsanger.gz | |||
| SRR14993664.fastq.gz | Fastqsanger.gz | |||
| SRR14993665.fastq.gz | Fastqsanger.gz |
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Project description:Decreasing the activation of pathology-activated microglia is crucial to prevent chronic inflammation and tissue scarring. In this study, we used a stab wound injury model in zebrafish and identified an injury-induced microglial state characterized by the accumulation of lipid droplets and TAR DNA-binding protein of 43 kDa (TDP-43)+ condensates. Granulin-mediated clearance of both lipid droplets and TDP-43+ condensates was necessary and sufficient to promote the return of microglia back to the basal state and achieve scarless regeneration. Moreover, in postmortem cortical brain tissues from patients with traumatic brain injury, the extent of microglial activation correlated with the accumulation of lipid droplets and TDP-43+ condensates. Together, our results reveal a mechanism required for restoring microglia to a nonactivated state after injury, which has potential for new therapeutic applications in humans.
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Project description:Single-nuclei Assay for Transposase-Accessible Chromatin with sequencing (snATACseq) was applied to examine chromatin landscape changes and transcriptional regulator (TR) DNA motif accessibility in reactive astrocytes following traumatic spinal cord injury (SCI). Astrocyte nuclei were isolated from the spinal cord of wild type mice and mice with astrocyte-specific conditional gene deletion (cKO) of test-case TRs, SMARCA4 (Smarca4-astro-cKO) or STAT3 knockout (Stat3-astro-cKO). Comparison of differential chromatin accessibility revealed substantial remodeling during astrocyte reactivity, with more chromatin opening than closing. Marked alterations in access to SCI reactivity-associated TR motifs were also detected.
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Project description:Most endogenous retroviruses (ERVs) in mammals are incapable of retrotransposition; therefore, why ERV de-repression is associated with lethality during early development has been a mystery. Here we report that rapid and selective degradation of the TRIM28 heterochromatin adapter protein triggers dissociation of transcriptional condensates from loci encoding super-enhancer -driven pluripotency genes, and their association with transcribed ERV loci in murine embryonic stem cells. Knockdown of ERV RNAs or forced expression of super-enhancer -enriched transcription factors rescued condensate localization at super-enhancers in TRIM28-degraded cells. In a biochemical reconstitution system, ERV RNA facilitated partitioning of RNA Polymerase II, and the Mediator co- activator into phase-separated droplets. In TRIM28 knockout mouse embryos, single-cell RNA-Seq analysis revealed specific depletion of pluripotent lineages. We propose that coding and non-coding nascent RNAs, including those produced by retrotransposons, may facilitate “hijacking” of transcriptional condensates in various developmental and disease contexts.
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Project description:Nine cigarette smoke condensates (CSCs) were produced under a standard ISO smoking machine regimen and one was produced by a more intense smoking machine regimen. These CSCs were used to treat primary normal human bronchial epithelial cells for 18 hours. Experiment Overall Design: Primary human bronchial/tracheal epithelial cells were grown in culture and treated with 10 different sources of cigarette smoke condensates.
2009-10-03 | E-GEOD-18235 | biostudies-arrayexpress
Project description:RNA sequencing was applied to examine changes in gene expression in reactive astrocytes following traumatic spinal cord injury (SCI) or neuroinflammatory insult by systemic administration of lipopolysaccharide (LPS). Transgenic Ribotag technology was used to isolate astrocyte ribosome-associated mRNAs from the spinal cord of wild type mice and mice with astrocyte-specific conditional gene deletion (cKO) of test-case transcriptional regulators of reactivity, SMARCA4 (Smarca4-astro-cKO) or STAT3 knockout (Stat3-astro-cKO). Examination of differentially expressed gene (DEG) profiles by upstream transcriptional regulator enrichment analysis (TREA) was used identify transcriptional regulators of reactivity in each condition. Together, findings from this study show that transcriptional changes associated with astrocyte reactivity are exquisitely heterogeneous and are customized from vast numbers of potential DEGs via context-specific combinatorial TR interactions. These data have also been made accessible in a open-access, searchable database: http://tr.astrocytereactivity.com
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Project description:TDP-43 is an RNA-binding protein ubiquitously dysregulated in neurodegeneration. We found that under stress conditions, TDP-43 undergoes reversible condensation in the nucleus of cultured cells including human neurons. These condensates (“TCs”) are non-liquid assemblies with low dynamic properties. Their proteomic analysis and subsequent comparison with the normal (soluble) TDP-43 interactome revealed that upon condensate partitioning, TDP-43 dissociates from its normal protein binding partners. We propose that the main function of TCs is rapid but reversible inactivation of TDP-43 during stress. This can help fine-tune the splicing patterns under stress to enable efficient stress response and survival.
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Project description:It remains largely unclear how material properties of biomolecular condensates impact physiological and pathological processes such as cancer. Here we show that AKAP95, a nuclear protein involved in gene regulation, plays an important role in tumorigenesis through directly regulating mRNA splicing. We show that AKAP95, through an intrinsic disordered region (IDR), forms liquid-like droplets in vitro and dynamic foci in nucleus. We have also identified key residues in IDR whose mutations to different residues perturb AKAP95 condensation in opposite directions. Importantly, the biological activity of AKAP95 in splice regulation is affected by either disruption of liquid condensation or enhancing the gelation of the assembly. We then show that the ability of AKAP95 in overcoming oncogene-induced senescence requires AKAP95 in an appropriate window of liquidity. These results thus link phase separation to tumorigenesis and uncover an important role of regulating the material property of protein condensates in disease including cancer.
2020-05-06 | GSE122308 | GEO
Project description:MicroRNAs (miRNAs) play important roles in a wide range of cellular processes. Aberrant regulation of miRNA genes contributes to human diseases, including cancer. The TAR DNA binding protein 43 (TDP-43), a DNA/RNA binding protein associated with neurodegeneration, is involved in miRNA biogenesis. Here, we systematically examined miRNAs whose expression levels are regulated by TDP-43 using RNA-Seq coupled with siRNA-mediated knockdown approach. TDP-43 knocking down affected the expression of a number of miRNAs. Alterations in isomiR patterns and miRNA arm selection after TDP-43 knockdown suggest a role of TDP-43 in miRNA editing. We examined correlation of selected TDP-43 associated miRNAs and their candidate target genes in human cancers. Our data reveal highly complex roles of TDP-43 in regulating different miRNAs and their target genes. Our results suggest that TDP-43 may promote migration of lung cancer cells by regulating miR-423-3p expression. On the other hand, TDP-43 increases miR-500a-3p expression and binds to the mature miR-500a-3p sequence. Low expression of miR-500a-3p was associated with poor survival of lung cancer patients, suggesting that TDP-43 may have a suppressive role in cancer by regulating miR-500a-3p. Our experiments reveal that cancer-associated genes LIF and PAPPA may be targets of miR-500a-3p. Together with other studies, our work suggests that TDP-43-regulated miRNAs may play multi-facet roles in the pathogenesis of cancer. small RNA seq in SH-SY-5Y, SNB-19 and HT22 (TDP-43 siRNA VS Control siRNA)
2016-08-02 | E-GEOD-85065 | biostudies-arrayexpress
Project description:Phase separation of biomolecules into condensates is a key mechanism in the spatiotemporal organization of biochemical processes in cells. We systematically engineered light-inducible transcription factor condensates with different material properties and analyzed their influence on transcription activation. When transcription factor condensates were transformed into solid-like gels, we observed a reduced activation of gene expression. We wanted to evaluate the impact that the condensate formation of the transcription factor RelA had on its endogenous promoters using expression data. To this aim, HEK-293T cells were transfected either with empty vector (1-3) or eGFP-RelA (4-6) or eGFP-RelA, Cry2olig-mCh-FUSN-NLS-NbGFP and Cry2olig-mCh-FUSN-NLS, along with an NF-κB-responsive SEAP reporter (7-9). In each of the three groups of transfected cells, 8 h after transfection, 3 samples were kept in the dark (D) and 3 under blue light illumination (BL, 5 μmol m-² s-1) for 24 h prior to RNA extraction. RNA-seq libraries from the 18 samples were sequenced by BGI on a DNBSEQ platform using paired-end chemistry with a read length of 100 base pairs each. Each strand was sequenced across two separate lanes (L03, L04), generating a total of 4 FASTQ files per sample.
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