Microtubule acetylation is required for mechanosensation in Drosophila
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PROVIDER: PRJNA492465 | ENA |
REPOSITORIES: ENA
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Project description:At the cellular level, α-tubulin acetylation alters the structure of microtubules to render them mechanically resistant to compressive forces. How this biochemical property of microtubule acetylation relates to mechanosensation remains unknown, though prior studies have shown that microtubule acetylation influences touch perception. Here, we identify the major Drosophila α-tubulin acetylase (dTAT) and show that it plays key roles in several forms of mechanosensation. dTAT is highly expressed in the larval peripheral nervous system (PNS), but is largely dispensable for neuronal morphogenesis. Mutation of the acetylase gene or the K40 acetylation site in α-tubulin impairs mechanical sensitivity in sensory neurons and behavioral responses to gentle touch, harsh touch, gravity, and vibration stimuli, but not noxious thermal stimulus. Finally, we show that dTAT is required for mechanically-induced activation of NOMPC, a microtubule-associated transient receptor potential channel, and functions to maintain integrity of the microtubule cytoskeleton in response to mechanical stimulation.
2018-09-22 | GSE120305 | GEO
Project description: Not available
| S-EPMC6248335 | biostudies-literature
Project description:The dynamic nature of the microtubule network is regulated in part by post-translational modifications – particularly through acetylation, which stabilizes the microtubule network. Whether post-translational modifications of the microtubule network in vascular smooth muscle cells contribute to the pathophysiology of hypertension is unknown. The aim of this study was to determine the acetylated state of the microtubule network in the mesenteric arteries of spontaneously hypertensive rats (SHR), and investigate whether sustained acetylation via treatment with a histone deacetlyase-6 (HDAC-6) inhibitor, tubacin, would affect isoprenaline-mediated vasorelaxations in normotensive and hypertensive vessels.Using Western blotting, and mass spectrometry, we show that acetylation of the microtubule network is increased in the mesenteric arteries of the SHR compared to normotensive rats. Using wire myography, we found that tubacin enhanced the β-adrenoceptor-mediated vasodilatation by isoprenaline when the endothelium was intact, but attenuated relaxations when the endothelium was denuded or nitric oxide production was inhibited. By pre-treating vessels with colchicine to disrupt the microtubule network, we were able to confirm that the effects of tubacin were microtubule-dependent. Using SICM, we examined the cell surface Young’s Modulus of smooth muscle cells, but found no difference between control, tubacin-treated, or taxol-treated cells.Acetylation of the microtubule network is elevated in mesenteric arteries from the SHR. Furthermore, this study shows that tubacin has an endothelial-dependent bimodal effect on isoprenaline-mediated vasorelaxation. These findings pave the way for evaluation of HDAC inhibitors in the treatment of hypertension in human clinical studies.
2024-02-21 | PXD045602 | Pride
Project description:We use closely-related Drosophila species to understand mechanosensation and how hearing as a form of mechanosensation drives reproductive isolation and evolution. In particular, we performed RNA-seq to obtain the Johnston's Organ transcriptomes of six closely-related Drosophila species, namely, D.melanogaster, D.yakuba, D.pseudoobscura and D.persimilis. Application of the Ornstein-Uhlenbeck model identified gene expression changes between the species' auditory structures. Motif discovery ( i-cisTarget and iRegulon) in differentially expressed genes in the oobscura group and melanogaster group on these transcriptomes identified thetranscription factor Hr39 as important for auditory differences among species. Hr39 is a nuclear hormone receptor important in song production and spermathecae development. Futher functional analyses Hr39 and many of its downstream targets are expressed in Johnston's Organ neurons. Hr39 mutants show sexually dimorphic defects in auditory mechanics and compound action potentials. These results indicate that Hr39 and its downstream regulon have a key role in Drosophila courtship behavior as a mechanism of reproductive isolation and evolution.
2020-07-05 | GSE100837 | GEO
Project description:Brain homeostasis is regulated by the viability and functionality of neurons. HAT (histone acetyltransferase) and HDAC (histone deacetylase) inhibitors have been applied to treat neurological deficits in humans; yet, the epigenetic regulation in neurodegeneration remains elusive. Mutations of HAT cofactor TRRAP (Transformation/translation domain-associated protein) cause human neuropathies, including psychosis, intellectual disability, autism and epilepsy, with unknown mechanism. Here we show that Trrap deletion in Purkinje neurons results in neurodegeneration of old mice. Integrated transcriptomics, epigenomics and proteomics reveal that TRRAP via SP1 conducts a conserved transcriptomic program. TRRAP is required for SP1 binding at the promoter proximity of target genes, especially microtubule dynamics. The ectopic expression of Stathmin3/4 ameliorates defects of TRRAP-deficient neurons, indicating that the microtubule dynamics is particularly vulnerable to the action of SP1 activity. This study unravels a network linking three well-known, but up-to-date unconnected, signaling pathways, namely TRRAP, HAT and SP1 with microtubule dynamics, in neuroprotection.
2021-03-02 | GSE131028 | GEO
Project description:Trimethylation of histone H3 lysine 4 (H3K4me3) accumulates at promoters in a gene activity dependant manner. The Set1 complex is responsible for most H3K4me3 in somatic cells and contains the conserved subunit Cfp1, which is implicated in targeting the Set1 complex to CpG islands in mammals. In mouse embryonic stem cells, Cfp1 is necessary for H3K4me3 accumulation at constitutively active gene promoters, but is not required to maintain steady-state transcription of the associated gene. Here we show that Cfp1 is instrumental for targeting H3K4me3 at promoters upon rapid transcriptional induction in response to external stimuli. Surprisingly, H3K4me3 accumulation is not required to ensure appropriate transcriptional output but rather plays gene specific roles. We also show that Cfp1 dependant H3K4me3 deposition contributes to H3K9 acetylation genome wide; suggesting that Cfp1 dependant H3K4me3 regulates overall H3K9 acetylation dynamics and is necessary for histone acetyl transferase recruitment. Finally, we observe increased antisense transcription at start and end of genes that requires Cfp1 for accurate H3K4me3 and H3K9ac deposition. Our results assign a key role for Cfp1 in establishing a complex active promoter chromatin state and shed light on how chromatin signalling pathways provide context dependant outcomes. wt (wtES) or Cfp1-/- (Cfp1null) ES cells were treated or not with doxorubicin (Dox) at 1uM for 6h. H3K4me3 (2 replicates) and H3K9,K14ac (H3ac, 1 replicate) occupancy was analyzed in each condition by ChIP-Seq. Input DNA for each cell line was alos sequenced alongside.
2014-08-20 | E-GEOD-53490 | biostudies-arrayexpress
Project description:The acquisition of cell invasiveness is the key transition from benign melanocyte hyperplasia to aggressive melanoma. Recent work using non-melanoma cancer cells has provided an intriguing new link between the presence of supernumerary centrosomes and increased cell invasion. Moreover, supernumerary centrosomes were shown to drive non-cell-autonomous invasion of cancer cells. Although centrosomes are the principle microtubule organizing centers the role of dynamic microtubules for non-cell-autonomous invasion remains unexplored, in particular in melanoma. We investigated the role of supernumerary centrosomes and dynamic microtubules in melanoma cell invasion and found that highly invasive melanoma cells are characterized by the presence of supernumerary centrosomes and by increased microtubule growth rates, both of which are functionally interlinked. We demonstrate that enhanced microtubule growth is required for increased 3D melanoma cell invasion. Moreover, we show that the activity to enhance microtubule growth can be transferred to adjacent non-invasive cells through extracellular vesicles harboring HER2 that are required for increased cell invasion of melanoma cells into 3D matrices. Hence, our study suggests that suppressing microtubule growth, either directly using anti-microtubule drugs or through HER2 inhibitors might be therapeutically beneficial to inhibit cell invasiveness and thus, metastasis of malignant melanoma.
2022-04-27 | PXD032224 | Pride
Project description:RREB1 regulates neuronal proteostasis and the microtubule network
2024-01-01 | GSE223878 | GEO
Project description:Old age is associated with a progressive decline of mitochondrial function and changes in nuclear chromatin. However, little is known about how metabolic activity and epigenetic modifications change as organisms reach their midlife. Here, we assessed how protein acetylation changes during midlife in Drosophila melanogaster. Midlife flies show elevated acetyl-CoA levels and alterations in protein acetylation. Based on these observations, we decreased the activity of the acetyl-CoA-synthesizing enzyme ATP citrate lyase (ATPCL). We find that lower ATPCL activity alleviates the observed aging-associated changes and promote longevity. Our findings reveal a pathway that couples changes of intermediate metabolism during aging with the chromatin-mediated regulation of transcription and changes in the activity of associated enzymes that modulate organismal lifespan.
2016-01-22 | PXD003318 | Pride
Project description:We report the acetylation of lysine residues in the globular domain of H3 (H3K64ac and H3K122ac) marks active gene promoters and also a subset of active enhancers in mouse embryonic stem cells (mESCs), human erythroleukemic cell line (K562). Moreover, we find a novel class of active functional enhancers in ESCs that are marked by H3K122ac but which lack H3K27ac. This work suggests that a more complex analysis of histone acetylation is required to identify enhancers than was previously considered. Examination of histone modifications in mouse ESCs (2 biological replicates) and K562 cells
2016-03-12 | E-GEOD-66023 | biostudies-arrayexpress