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Fig. 4 | Epigenetics & Chromatin

Fig. 4

From: Multiple distinct domains of human XIST are required to coordinate gene silencing and subsequent heterochromatin formation

Fig. 4

Examining the connections between XIST-dependent chromatin modifiers. AD The relative distribution of chromatin features following chemical inhibition (59–61 cells each) are shown plotted according to the chemical inhibitor used. The median z-score of uninhibited Full XIST cells is shown as a dotted red line to provide a point of comparison. All conditions were blinded throughout the process and comparisons were made using the Mann–Whitney test with multiple testing correction (p-values * < 0.05, ** < 0.01, *** < 0.001). A Cells were treated with 1uM RGFP966 to inhibit HDAC3. B Cells were treated with 60 nM TSA to broadly inhibit HDACs. C Cells were treated with 4uM of ryuvidine to inhibit KMT5A. D Cells were treated with either PRC2 inhibitor GSK343 (5 µM) or PRC1 inhibitor PRT4165 (50 µM). E Summary of the functions of XIST domains with connections between the various chromatin-remodelling factors studied (created with BioRender.com). The hashed colours depict the dependence of MacroH2A on PRC2 activity and SMCHD1 on PRC1. Pointed arrows indicate activation or contribution to a process, flat-headed arrows indicate inhibition. Solid arrows indicate an essential role while dotted arrows indicate effects that are only modestly contributing to a process. The depiction on the right shows our model of how the A, F and E repeats contribute to gene silencing and the spread of H3K27me3. The Repeat F region is essential for aggregation to repressed domains, including pre-existing H3K27me3 regions. This brings Repeat A into proximity of expressed genes (resulting in their silencing); and brings Repeat E (and bound proteins like CIZ1) together to facilitate spread of H3K27me3 along the chromosome. However, Repeat E is not necessary for silencing, and Repeat A is not necessary for H3K27me3 recruitment. Repeat E facilitates the activation and/or recruitment of PRC2 to promote the spread of H3K27me3

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