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. 2023 Mar 27;14:1694. doi: 10.1038/s41467-023-37398-9

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© The Author(s) 2023

Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

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Fig. 4 — a Epigenomics Roadmap indicates that genes with H3K4me3 peaks in their promoter regions are enriched in LFS astrocytes. b Word clouds represent proteins inferred with high confidence to interact with SVIL in LFS astrocytes. c Endogenous interaction between SVIL and MLL1 in LFS-GFP-SVIL astrocytes. d PLA analysis indicates that endogenous mutant p53 forms a complex with SVIL and MLL1 in LFS astrocytes. Scale bar, 10 µm. e Depletion of SVIL impairs p53(G245D)/SVIL/MLL1 complex formation in LFS astrocytes. f Depletion of SVIL impairs mutant p53/SVIL/MLL1 complex formation. Scale bar, 10 µm. g H3K4me3 peaks on the YTHDF2 promoter are reduced upon MLL1 depletion or MLL1 inhibition by OICR-9429 in LFS astrocytes. h RT-qPCR analysis demonstrates decreased YTHDF2 mRNA expression upon MLL1 knockdown in LFS astrocytes but not WT astrocytes (n = 3 biologically independent samples). i Immunoblotting indicates reduced YTHDF2 protein upon the treatment with MLL1 inhibitors OICR-9429 and MI-2-2 in LFS astrocytes. j OICR-9429 and MI-2-2 selectively inhibit cell proliferation of LFS astrocytes (n = 5 biologically independent samples). k In vitro AIG assay demonstrates decreased colony numbers upon MLL1 depletion in LFS astrocytes (n = 5 biologically independent samples). l Ectopic YTHDF2 expression rescues SVIL or MLL1 knockdown-induced growth inhibition in LFS astrocytes (n = 6 biologically independent samples). m In vitro AIG assay demonstrates decreased colony numbers upon SVIL or MLL1 knockdown that are rescued by YTHDF2 expression (n = 3 biologically independent samples)). n Colony-forming assay demonstrates that OICR-9429 and MI-2-2 cause more severe growth inhibition of LNZ308-p53(G245D) cells than LNZ308-Vector cells (n = 3 biologically independent samples). o Images of WT (mCherry⁺) and LFS (GFP⁺) co-cultured cerebral organoids examined by light sheet fluorescence microscopy. Scale bar, 500 µm. p OICR-9429 selectively inhibits proliferation of the LFS-derived population of WT/LFS co-cultured cerebral organoids (n = 19 biologically independent samples). The results are representative of at least three independent experiments (c–f, i, o). The data are presented as the mean ± SEM; two-way ANOVA with Bonferroni’s multiple comparison test (h, j–n); unpaired two-tailed Student’s t test (p); ***P < 0.001. ns not significant. Source data and exact P values are provided in the Source Data file.