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Project description:MBD1 activates neuronal developmental genes through modulating chromatin structure during neuronal maturation
| PRJNA386939 | ENA
Project description:BackgroundChromatin provides a tunable platform for gene expression control. Besides the well-studied core nucleosome, H1 linker histones are abundant chromatin components with intrinsic potential to influence chromatin function. Well studied in animals, little is known about the evolution of H1 function in other eukaryotic lineages for instance plants. Notably, in the model plant Arabidopsis, while H1 is known to influence heterochromatin and DNA methylation, its contribution to transcription, molecular, and cytological chromatin organization remains elusive.ResultsWe provide a multi-scale functional study of Arabidopsis linker histones. We show that H1-deficient plants are viable yet show phenotypes in seed dormancy, flowering time, lateral root, and stomata formation-complemented by either or both of the major variants. H1 depletion also impairs pluripotent callus formation. Fine-scale chromatin analyses combined with transcriptome and nucleosome profiling reveal distinct roles of H1 on hetero- and euchromatin: H1 is necessary to form heterochromatic domains yet dispensable for silencing of most transposable elements; H1 depletion affects nucleosome density distribution and mobility in euchromatin, spatial arrangement of nanodomains, histone acetylation, and methylation. These drastic changes affect moderately the transcription but reveal a subset of H1-sensitive genes.ConclusionsH1 variants have a profound impact on the molecular and spatial (nuclear) chromatin organization in Arabidopsis with distinct roles in euchromatin and heterochromatin and a dual causality on gene expression. Phenotypical analyses further suggest the novel possibility that H1-mediated chromatin organization may contribute to the epigenetic control of developmental and cellular transitions.
| S-EPMC6685187 | biostudies-literature
Project description:We found that glia secrete myoglianin, a TGF-? ligand, to instruct developmental neural remodeling in Drosophila. Glial myoglianin upregulated neuronal expression of an ecdysone nuclear receptor that triggered neurite remodeling following the late-larval ecdysone peak. Thus glia orchestrate developmental neural remodeling not only by engulfment of unwanted neurites but also by enabling neuron remodeling.
| S-EPMC3337551 | biostudies-literature
Project description:Neuronal nitric oxide synthase is involved in diverse signaling cascades that regulate neuronal development and functions via S-Nitrosylation-mediated mechanism or the soluble guanylate cyclase (sGC)/cyclic guanosine monophosphate (cGMP) pathway activated by nitric oxide. Although it has been studied extensively in vitro and in invertebrate animals, effects on mammalian brain development and underlying mechanisms remain poorly understood. Here we report that genetic deletion of "Nos1" disrupts dendritic development, whereas pharmacological inhibition of the sGC/cGMP pathway does not alter dendritic growth during cerebral cortex development. Instead, nuclear distribution element-like (NDEL1), a protein that regulates dendritic development, is specifically S-nitrosylated at cysteine 203, thereby accelerating dendritic arborization. This post-translational modification is enhanced by N-methyl-D-aspartate receptor-mediated neuronal activity, the main regulator of dendritic formation. Notably, we found that disruption of S-Nitrosylation of NDEL1 mediates impaired dendritic maturation caused by developmental alcohol exposure, a model of developmental brain abnormalities resulting from maternal alcohol use. These results highlight S-Nitrosylation as a key activity-dependent mechanism underlying neonatal brain maturation and suggest that reduction of S-Nitrosylation of NDEL1 acts as a pathological factor mediating neurodevelopmental abnormalities caused by maternal alcohol exposure.
| S-EPMC6248727 | biostudies-literature
Project description:MBD1 belongs to a family of mammalian proteins that share a methyl-CpG binding domain. Previous work has shown that MBD1 binds to methylated sites in vivo and in vitro and can repress transcription from methylated templates in transcription extracts and in cultured cells. In the present study we established by several experimental criteria that, contrary to a previous report, MBD1 is not a component of the MeCP1 repressor complex. We identified a powerful transcriptional repression domain (TRD) at the C terminus of MBD1 that can actively repress transcription at a distance. Methylation-dependent repression in vivo depends on the presence of both the TRD and the methyl-CpG binding domain. The mechanism is likely to involve deacetylation, since the deacetylase inhibitor trichostatin A can overcome MBD1-mediated repression. Accordingly, we found that endogenous MBD1 is particularly concentrated at sites of centromeric heterochromatin, where acetylated histone H4 is deficient. Unlike MBD2 and MeCP2, MBD1 is not depleted by antibodies to the histone deacetylase HDAC1. Thus, the deacetylase-dependent pathway by which MBD1 actively silences methylated genes is likely to be different from that utilized by the methylation-dependent repressors MeCP1 and MeCP2.
| S-EPMC85293 | biostudies-literature
Project description:Specification of tissue identity during development requires precise coordination of gene expression in both space and time. Spatially, master regulatory transcription factors are required to control tissue-specific gene expression programs. However, the mechanisms controlling how tissue-specific gene expression changes over time are less well understood. Here, we show that hormone-induced transcription factors control temporal gene expression by regulating the accessibility of DNA regulatory elements. Using the Drosophila wing, we demonstrate that temporal changes in gene expression are accompanied by genome-wide changes in chromatin accessibility at temporal-specific enhancers. We also uncover a temporal cascade of transcription factors following a pulse of the steroid hormone ecdysone such that different times in wing development can be defined by distinct combinations of hormone-induced transcription factors. Finally, we show that the ecdysone-induced transcription factor E93 controls temporal identity by directly regulating chromatin accessibility across the genome. Notably, we found that E93 controls enhancer activity through three different modalities, including promoting accessibility of late-acting enhancers and decreasing accessibility of early-acting enhancers. Together, this work supports a model in which an extrinsic signal triggers an intrinsic transcription factor cascade that drives development forward in time through regulation of chromatin accessibility.
| S-EPMC5458754 | biostudies-literature
Project description:Glia engulf and phagocytose neurons during neural circuit developmental remodeling. Disrupting this pruning process contributes to Fragile X syndrome (FXS), a leading cause of intellectual disability and autism spectrum disorder in mammals. Utilizing a Drosophila FXS model central brain circuit, we identify two glial classes responsible for Draper-dependent elimination of developmentally transient PDF-Tri neurons. We find that neuronal Fragile X Mental Retardation Protein (FMRP) drives insulin receptor activation in glia, promotes glial Draper engulfment receptor expression, and negatively regulates membrane-molding ESCRT-III Shrub function during PDF-Tri neuron clearance during neurodevelopment in Drosophila. In this context, we demonstrate genetic interactions between FMRP and insulin receptor signaling, FMRP and Draper, and FMRP and Shrub in PDF-Tri neuron elimination. We show that FMRP is required within neurons, not glia, for glial engulfment, indicating FMRP-dependent neuron-to-glia signaling mediates neuronal clearance. We conclude neuronal FMRP drives glial insulin receptor activation to facilitate Draper- and Shrub-dependent neuronal clearance during neurodevelopment in Drosophila.
| S-EPMC7896095 | biostudies-literature
Project description:During neocortical development, newborn neurons migrate along radial fibers from the germinal ventricular zone (VZ) toward the cortical plate (CP) to populate the cerebral cortex. This radial migration requires adhesion activities between neurons and radial fibers; however, past research has identified only a limited number of adhesion molecules involved in this process. Contactin-1/F3 (Cntn1), a cell adhesion molecule expressed in the developing nervous system is essential for many key developmental events including neural cell adhesion, neurite outgrowth, axon guidance and myelination. However, the potential role of Cntn1 in neuronal migration during cortical development has not been investigated. Here we used in utero electroporation to introduce short hairpin RNA (shRNA) to knock down (KD) Cntn1 in neural stem cells in vivo. We found that Cntn1 KD led to a delay in neuronal migration. The arrested cells presented abnormal morphology in their leading process and more multipolar cells were observed in the deep layers of the brain, suggestive of dysregulation in process formation. Intriguingly, Cntn1 KD also resulted in upregulation of RhoA, a negative regulator for neuronal migration. Interference of RhoA by expression of the dominant-negative RhoAN19 partially rescued the neuronal migration defects caused by Cntn1 KD. Our results showed that Cntn1 is a novel adhesion protein that is essential for neuronal migration and regulates process formation of newborn cortical neurons through modulating RhoA signaling pathway.
| S-EPMC6255823 | biostudies-literature
Project description:Higher order folding of chromatin fibre is mediated by interactions of the histone H4 N-terminal tail domains with neighbouring nucleosomes. Mechanistically, the H4 tails of one nucleosome bind to the acidic patch region on the surface of adjacent nucleosomes, causing fibre compaction. The functionality of the chromatin fibre can be modified by proteins that interact with the nucleosome. The co-structures of five different proteins with the nucleosome (LANA, IL-33, RCC1, Sir3 and HMGN2) recently have been examined by experimental and computational studies. Interestingly, each of these proteins displays steric, ionic and hydrogen bond complementarity with the acidic patch, and therefore will compete with each other for binding to the nucleosome. We first review the molecular details of each interface, focusing on the key non-covalent interactions that stabilize the protein-acidic patch interactions. We then propose a model in which binding of proteins to the nucleosome disrupts interaction of the H4 tail domains with the acidic patch, preventing the intrinsic chromatin folding pathway and leading to assembly of alternative higher order chromatin structures with unique biological functions.
| S-EPMC3627075 | biostudies-literature
Project description:Several recent studies have examined different aspects of mammalian higher order chromatin structure - replication timing, lamina association and Hi-C inter-locus interactions - and have suggested that most of these features of genome organisation are conserved over evolution. However, the extent of evolutionary divergence in higher order structure has not been rigorously measured across the mammalian genome, and until now little has been known about the characteristics of any divergent loci present. Here, we generate a dataset combining multiple measurements of chromatin structure and organisation over many embryonic cell types for both human and mouse that, for the first time, allows a comprehensive assessment of the extent of structural divergence between mammalian genomes. Comparison of orthologous regions confirms that all measurable facets of higher order structure are conserved between human and mouse, across the vast majority of the detectably orthologous genome. This broad similarity is observed in spite of many loci possessing cell type specific structures. However, we also identify hundreds of regions (from 100 Kb to 2.7 Mb in size) showing consistent evidence of divergence between these species, constituting at least 10% of the orthologous mammalian genome and encompassing many hundreds of human and mouse genes. These regions show unusual shifts in human GC content, are unevenly distributed across both genomes, and are enriched in human subtelomeric regions. Divergent regions are also relatively enriched for genes showing divergent expression patterns between human and mouse ES cells, implying these regions cause divergent regulation. Particular divergent loci are strikingly enriched in genes implicated in vertebrate development, suggesting important roles for structural divergence in the evolution of mammalian developmental programmes. These data suggest that, though relatively rare in the mammalian genome, divergence in higher order chromatin structure has played important roles during evolution.
| S-EPMC3617018 | biostudies-literature