The LINC Complex Inhibits Excessive Chromatin Repression

Abstract

The Linker of Nucleoskeleton and Cytoskeleton (LINC) complex transduces nuclear mechanical inputs suggested to control chromatin organization and gene expression; however, the underlying mechanism is currently unclear. We show here that the LINC complex is needed to minimize chromatin repression in muscle tissue, where the nuclei are exposed to significant mechanical inputs during muscle contraction. To this end, the genomic binding profiles of Polycomb, Heterochromatin Protein1 (HP1a) repressors, and of RNA-Pol II were studied in Drosophila larval muscles lacking functional LINC complex. A significant increase in the binding of Polycomb and parallel reduction of RNA-Pol-II binding to a set of muscle genes was observed. Consistently, enhanced tri-methylated H3K9 and H3K27 repressive modifications and reduced chromatin activation by H3K9 acetylation were found. Furthermore, larger tri-methylated H3K27me3 repressive clusters, and chromatin redistribution from the nuclear periphery towards nuclear center, were detected in live LINC mutant larval muscles. Computer simulation indicated that the observed dissociation of the chromatin from the nuclear envelope promotes growth of tri-methylated H3K27 repressive clusters. Thus, we suggest that by promoting chromatin–nuclear envelope binding, the LINC complex restricts the size of repressive H3K27 tri-methylated clusters, thereby limiting the binding of Polycomb transcription repressor, directing robust transcription in muscle fibers.

A polymer-physics view of peripheral chromatin: de Gennes’ self-similar carpet

“…In general, as shown in Fig. 4a, decreasing chromatin concentration with increasing distance from the nuclear periphery is a common hallmark of the density profiles in all simulations and experiments [35,[71][72][73][74][75][76][77][78][79] and agrees well with our model, see Eq. ( 9) and Fig.…”

“…The nuclear chromatin density profiles were often reported in the fluorescence-intensity units or arbitrary units for each cell type as a function of nuclear radial distance [35,[65][66][67][68][69][70][71][72][73]. Therefore, to compare our results summarized in Eqs.…”

Histone Modification of Osteogenesis Related Genes Triggered by Substrate Topography Promotes Human Mesenchymal Stem Cell Differentiation

“…The cytoskeleton network bridges the cell membrane and the nucleus through the linker of nucleoskeleton and cytoskeleton (LINC) complex. − In this way, the mechanical signals could be directly transmitted from the cell/material interface to the nucleus . Compared to the relaxed nucleus under low intracellular tension, the mechanically stressed nucleus deformed as a response to the high contractile force .…”

A computational pipeline for identifying gene targets and signalling pathways in cancer cells to improve lymphocyte infiltration and immune checkpoint therapy efficacy

“… 58 , 59 , 60 All the evidence suggests that our identified genes and pathways are worth further exploration and validation, and can potentially be developed for immunotherapeutic interference. Importantly, we validated SUN1, which is a component of the LINC complex that links the nucleoskeleton (i.e., nuclear lamina) and cytoskeleton, 61 , 62 and important for chromatin/chromosome organisation, mRNA transport, and transcriptional regulation, 63 , 64 to have a new role in anti-tumour immunity. Single-cell multiome analysis identified a sub-GRN showing Stat proteins like Stat1/2/3 are master regulators for the antigen processing and presentation and type I interferon related pathways.…”