dynamic regulation
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2022 ◽  
Vol 51 ◽  
pp. 101917
Author(s):  
Yiwen Liao ◽  
Weijia Yang ◽  
Zhigao Zhao ◽  
Xudong Li ◽  
Xiaohu Ci ◽  
...  

2022 ◽  
Author(s):  
Samuel Thudium ◽  
Katherine C Palozola ◽  
Eloise L'Her ◽  
Erica Korb

Epigenetic regulation plays a critical role in many neurodevelopmental disorders, including Autism Spectrum Disorder (ASD). In particular, many such disorders are the result of mutations in genes that encode chromatin modifying proteins. However, while these disorders share many features, it is unclear whether they also share gene expression disruptions resulting from the aberrant regulation of chromatin. We examined 5 chromatin modifiers that are all linked to ASD despite their different roles in regulating chromatin. Specifically, we depleted Ash1L, Chd8, Crebbp, Ehmt1, and Nsd1 in parallel in a highly controlled neuronal culture system. We then identified sets of shared genes, or transcriptional signatures, that are differentially expressed following loss of multiple ASD-linked chromatin modifiers. We examined the functions of genes within the transcriptional signatures and found an enrichment in many neurotransmitter transport genes and activity-dependent genes. In addition, these genes are enriched for specific chromatin features such as bivalent domains that allow for highly dynamic regulation of gene expression. The downregulated transcriptional signature is also observed within multiple mouse models of neurodevelopmental disorders that result in ASD, but not those only associated with intellectual disability. Finally, the downregulated transcriptional signature can distinguish between neurons generated from iPSCs derived from healthy donors and idiopathic ASD patients through RNA-deconvolution, demonstrating that this gene set is relevant to the human disorder. This work identifies a transcriptional signature that is found within many neurodevelopmental syndromes, helping to elucidate the link between epigenetic regulation and the underlying cellular mechanisms that result in ASD.


2022 ◽  
Vol 12 ◽  
Author(s):  
Ritesh Kumar Srivastava ◽  
Bharat Mishra ◽  
Suhail Muzaffar ◽  
Marina S. Gorbatyuk ◽  
Anupam Agarwal ◽  
...  

The use of chemical warfare agents is prohibited but they have been used in recent Middle Eastern conflicts. Their accidental exposure (e.g. arsenical lewisite) is also known and causes extensive painful cutaneous injury. However, their molecular pathogenesis is not understood. Here, we demonstrate that a nexus of stress granules (SGs), integrated stress, and RNA binding proteins (RBPs) Roquin and Reganse-1 play a key role. Lewisite and its prototype phenylarsine oxide (PAO) induce SG assembly in skin keratinocytes soon after exposure, which associate with various RBPs and translation-related proteins. SG disassembly was detected several hours after exposure. The dynamics of SG assembly-disassembly associates with the chemical insult and cell damage. Enhanced Roquin and Regnase-1 expression occurs when Roquin was recruited to SGs and Regnase-1 to the ribosome while in the disassembling SGs their expression is decreased with consequent induction of inflammatory mediators. SG-targeted protein translational control is regulated by the phosphorylation-dependent activation of eukaryotic initiation factors 2α (eIF2α). Treatment with integrated stress response inhibitor (ISRIB), which blocks eIF2α phosphorylation, impacted SG assembly dynamics. Topical application of ISRIB attenuated the inflammation and tissue disruption in PAO-challenged mice. Thus, the dynamic regulation of these pathways provides underpinning to cutaneous injury and identify translational therapeutic approach for these and similar debilitating chemicals.


eLife ◽  
2022 ◽  
Vol 11 ◽  
Author(s):  
Julien Gronnier ◽  
Christina M Franck ◽  
Martin Stegmann ◽  
Thomas A DeFalco ◽  
Alicia Abarca ◽  
...  

Spatial partitioning is a propensity of biological systems orchestrating cell activities in space and time. The dynamic regulation of plasma membrane nano-environments has recently emerged as a key fundamental aspect of plant signaling, but the molecular components governing it are still mostly unclear. The receptor kinase FERONIA (FER) controls ligand-induced complex formation of the immune receptor kinase FLAGELLIN SENSING 2 (FLS2) with its co-receptor BRASSINOSTEROID INSENSITIVE 1-ASSOCIATED KINASE 1 (BAK1), and perception of the endogenous peptide hormone RAPID ALKALANIZATION FACTOR 23 (RALF23) by FER inhibits immunity. Here, we show that FER regulates the plasma membrane nanoscale organization of FLS2 and BAK1. Our study demonstrates that akin to FER, leucine-rich repeat (LRR) extensin proteins (LRXs) contribute to RALF23 responsiveness, regulate BAK1 nanoscale organization and immune signaling. Furthermore, RALF23 perception leads to rapid modulation of FLS2 and BAK1 nanoscale organization, and its inhibitory activity on immune signaling relies on FER kinase activity. Our results suggest that perception of RALF peptides by FER and LRXs actively modulates plasma membrane nanoscale organization to regulate cell surface signaling by other ligand-binding receptor kinases.


2022 ◽  
Author(s):  
Adrien Méry ◽  
Artur Ruppel ◽  
Jean Révilloud ◽  
Martial Balland ◽  
Giovanni Cappello ◽  
...  

The mechanical properties of biological tissues are key to the regulation of their physical integrity and function. Although the application of external loading or biochemical treatments allows to estimate these properties globally, it remains problematic to assess how such external stimuli compare with internal, cell-generated contractions. Here we engineered 3D microtissues composed of optogenetically-modified fibroblasts encapsulated within collagen. Using light to control the activity of RhoA, a major regulator of cellular contractility, we induced local mechanical perturbation within 3D fibrous microtissues, while tracking in real time microtissue stress and strain. We thus investigated the dynamic regulation of light-induced, local contractions and their spatio-temporal propagation in microtissues. By comparing the evolution of stresses and strains upon stimulation, we demonstrated the potential of our technique for quantifying tissue elasticity and viscosity, before examining the possibility of using light to map local anisotropies in mechanically heterogeneous microtissues. Altogether, our results open an avenue to non-destructively chart the rheology of 3D tissues in real time, using their own constituting cells as internal actuators.


Author(s):  
Ari Dwijayanti ◽  
Congqiang Zhang ◽  
Chueh Loo Poh ◽  
Thomas Lautier

Owing to its ubiquity and easy availability in nature, light has been widely employed to control complex cellular behaviors. Light-sensitive proteins are the foundation to such diverse and multilevel adaptive regulations in a large range of organisms. Due to their remarkable properties and potential applications in engineered systems, exploration and engineering of natural light-sensitive proteins have significantly contributed to expand optogenetic toolboxes with tailor-made performances in synthetic genetic circuits. Progressively, more complex systems have been designed in which multiple photoreceptors, each sensing its dedicated wavelength, are combined to simultaneously coordinate cellular responses in a single cell. In this review, we highlight recent works and challenges on multiplexed optogenetic circuits in natural and engineered systems for a dynamic regulation breakthrough in biotechnological applications.


2022 ◽  
Author(s):  
Alberto Granzotto ◽  
Marco d'Aurora ◽  
Manuela Bomba ◽  
Valentina Gatta ◽  
Marco Onofrj ◽  
...  

Excitotoxicity is a form of neuronal death characterized by the sustained activation of N-methyl-D-aspartate receptors (NMDARs) triggered by the excitatory neurotransmitter glutamate. NADPH-diaphorase neurons [also known as nNOS (+) neurons] are a subpopulation of aspiny interneurons, largely spared following excitotoxic challenges. Unlike nNOS (-) cells, nNOS (+) neurons fail to generate reactive oxygen species in response to NMDAR activation, a key divergent step in the excitotoxic cascade. However, additional mechanisms underlying the reduced vulnerability of nNOS (+) neurons to NMDAR-driven neuronal death have not been explored. Using functional, genetic, and molecular analysis in striatal cultures, we demonstrate that nNOS (+) neurons possess distinct NMDAR properties. These specific features are primarily driven by the peculiar redox milieu of this subpopulation. In addition, we found that nNOS (+) neurons exposed to a pharmacological maneuver set to mimic chronic excitotoxicity alter their responses to NMDAR-mediated challenges. These findings suggest the presence of mechanisms providing long-term dynamic regulation of NMDARs that can have critical implications in neurotoxic settings.


Cells ◽  
2021 ◽  
Vol 11 (1) ◽  
pp. 79
Author(s):  
Giorgia Giordani ◽  
Valeria Cavaliere ◽  
Giuseppe Gargiulo ◽  
Giovanna Lattanzi ◽  
Davide Andrenacci

The transposon theory of aging hypothesizes the activation of transposable elements (TEs) in somatic tissues with age, leading to a shortening of the lifespan. It is thought that TE activation in aging produces an increase in DNA double-strand breaks, contributing to genome instability and promoting the activation of inflammatory responses. To investigate how TE regulation changes in somatic tissues during aging, we analyzed the expression of some TEs, as well as a source of small RNAs that specifically silence the analyzed TEs; the Drosophila cluster named flamenco. We found significant variations in the expression levels of all the analyzed TEs during aging, with a trend toward reduction in middle-aged adults and reactivation in older individuals that suggests dynamic regulation during the lifespan.


Author(s):  
Hengzhen Li ◽  
WenFeng Xiao ◽  
Yuqiong He ◽  
Zeqin Wen ◽  
Siyuan Cheng ◽  
...  

N6-methyladenosine (m6A) is an important modification of eukaryotic mRNA. Since the first discovery of the corresponding demethylase and the subsequent identification of m6A as a dynamic modification, the function and mechanism of m6A in mammalian gene regulation have been extensively investigated. “Writer”, “eraser” and “reader” proteins are key proteins involved in the dynamic regulation of m6A modifications, through the anchoring, removal, and interpretation of m6A modifications, respectively. Remarkably, such dynamic modifications can regulate the progression of many diseases by affecting RNA splicing, translation, export and degradation. Emerging evidence has identified the relationship between m6A modifications and degenerative musculoskeletal diseases, such as osteoarthritis, osteoporosis, sarcopenia and degenerative spinal disorders. Here, we have comprehensively summarized the evidence of the pathogenesis of m6A modifications in degenerative musculoskeletal diseases. Moreover, the potential molecular mechanisms, regulatory functions and clinical implications of m6A modifications are thoroughly discussed. Our review may provide potential prospects for addressing key issues in further studies.


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