Fig 2: Regulation of mevalonate pathway by ARID1A. Schematic diagram of mevalonate pathway based on IPA curation. Canonical pathways overrepresented upon ARID1A knockout in OVCA429 and induction in OVISE are labeled. Blue: enzymes significantly decreased in abundance in knockout and significantly increased in abundance in induction. For enzymes that significantly changed in one condition, we allowed for a slightly relaxed fold change in the other condition (i.e. 1.8-fold change with Student's t test p < 0.05). Red: enzymes significantly increased in abundance in induction and not significantly changed in knockout. Refer to Table I.

Fig 3: Acute Arid1a knockdown induces rapid changes in acinar cell fate in the setting of KrasG12D.(A) Kaplan-Meier curve of KC-RIK-shRen and –shArid1a cohort after dox administration. (B) H and E staining of KC-RIK-shRen and –shArid1a mice after 2 weeks on dox. Top panels, scalebar 600 μm; bottom panels, scalebar 200 μm. (C) Immunohistochemistry staining for the ductal marker Sox9 in KC-RIK-shRen and –shArid1a pancreas. Alcian blue counterstain stains acidic mucins in mucinous lesions. Scalebar 100 μm. (D) Quantification of ADM, PanIN, and IPMN lesions per mm2 of tissue area measured by a veterinary pathologist blinded to genotype, comparing the shRen animals with the 2 Arid1a shRNA groups in the Arid1a KD genotype. p<0.05. Each dot represents one animal. (E) Immunofluorescence staining KC-RIK-shRen and –shArid1a tissue for the acinar marker Carboxypeptidase 1 (Cpa1) and GFP. Nuclei are labeled with DAPI. Scalebar 100 μm.Quantification of Cpa1 staining within GFP +area in panel (F). p<0.0001. At least three animals per condition were used for histological quantification experiments.10.7554/eLife.35216.008Figure 2—source data 1.Quantification of pancreatic lesions upon acute Arid1a knockdown.

Fig 4: Characterization of tumor-infiltrating immune cells based on ARID1A and CD47 expression. (A) Estimation of tumor-infiltrating immune cells in different subgroups stratified by ARID1A status and CD47 expression. (B) Multiplex immunofluorescent images illustrate GC tissues with ARID1AlossCD47high or ARID1ApreservedCD47low expression that express CD11c, CD163, and Foxp3. (C) Quantitative analysis of the densities of immune markers between ARID1AlossCD47high and ARID1ApreservedCD47low GC tissues. Error bars represent mean with SD. *p < 0.05, **p < 0.01, ***p < 0.001.

Fig 5: ARID1A deficiency promotes liver cancer cell metastasis via dysregulation on PMP22 and GSC.A Immunoblotting on Pmp22 and Gsc in liver tissues of 3 and 14 month old Arid1afl/fl mice and Arid1aLKO littermates. B Representative IHC staining (Left) and quantification of positive staining (Right) for Pmp22 and Gsc in liver tissues of 3-month-old Arid1afl/fl mice and Arid1aLKO littermates. Scale bar = 50 μm. Data are presented as the mean ± SEM (n = 5 per group). *p < 0.05, **p < 0.01, calculated by a two-tailed Student’s t-test. C Representative images of invasive MHCC-97H cells transfected with Pcdh-PMP22 construct; lentiviral shARID1A-1, and ARID1A-knockdown cells co-transfected with Pcdh-PMP22 in transwell assays (Scale bar, 100 µm) (Left) and quantification of the invasive cells (Right). Data are shown as mean ± SEM of three independent experiments. *p < 0.05, **p < 0.01, calculated by a two-tailed Student’s t-test. D Representative images and quantification of the invasive MHCC-97H cells treated with the indicated lentiviral shRNA plasmids for ARID1A (shARID1A-1) and GSC (shGSC-1) in transwell assays. E The relapse-free survival and the overall survival in HCC patients with high or low expression of PMP22 (Left) and GSC (Right), examined by Kaplan-Meier analysis. F Schematic diagram of the dysregulated mechanism related to PMP22 and GSC loci upon ARID1A deficiency. Based on our data, we proposed the working model of the SWI/SNF complex in maintaining chromatin organization mediated by the BRG1-RAD21 axis in hepatocytes. Once ARID1A is deficient, the chromatin loop tethering promoter to the enhancer of Pmp22 might be weakened due to the attenuated anchorage force arising from insufficient BRG1 (Top); the unaided boundaries lead to TAD remodeling surrounding Gsc locus to some extent (Bottom).