Fig. 5
From: SMARCA4 loss is synthetic lethal with CDK4/6 inhibition in non-small cell lung cancer
SMARCA4/2 regulate CCND1 via controlling chromatin accessibility and upregulating JUN. a Assay for transposase-accessible chromatin sequencing (ATAC-seq) and chromatin immunoprecipitation sequencing (ChIP-seq) data in vicinity of the CCND1 locus indicate enhanced chromatin accessibility upon SMARCA4/2 restoration. Note SMARCA4 at CCND1 promoter and formation of new putative enhancer ~50 kb upstream of CCND1 promoter. All data were generated in H1703 cells before and after restoration of SMARCA4 or SMARCA2, except the publicly available SMARCA4 ChIP data in H1299 cells expressing doxycycline (Dox)-inducible SMARCA434. Track height is normalized to relative number of mapped reads. b Zoomed-in view of the putative CCND1 enhancer region. Shown are ATAC-seq peaks in H1703 cells before and after SMARCA4/2 restoration and the publicly available c-Fos/c-Jun ChIP data of endothelial cell line, human umbilical vein endothelial cell (HUVEC) (GSM935585, GSM935278). Location of canonical adaptor protein-1 (AP-1) motifs are indicated. c ATAC and ChIP-seq data in vicinity of JUN locus as described in a. Note SMARCA4 at JUN promoter and extensive opening of nearby putative enhancers. d–i Restoration of SMARCA4 in H1703 (d, e) and H1299 (f, g) or SMARCA2 restoration in H1703 (h, i) cells upregulate c-Jun messenger RNA (mRNA) (d, f, h) and protein (e, g, i). j, k Knockdown of JUN partially abrogated SMARCA4-mediated induction of cyclin D1 mRNA (j) and protein (k) expression in H1703 cells. l Proposed model showing that SMARCA4 directly regulates CCND1 and also upregulates JUN which positively regulates CCND1. Two-tailed t-test. Error bars represent mean ± s.d., ***p < 0.001, ****p < 0.0001
