PAXIP1 and STAG2-cohesin regulation of gene expression and chromatin accessibility is conserved in downregulation but not upregulation of genes. (a) PCA of RNA-seq on KT;H11^LSL-Cas9 sgInert and KT;H11^LSL-Cas9 sgPaxip1 tumors. (b) Upregulated PAXIP1 gene signature enrichment in rank-ordered gene list for KT versus KT;Stag2^flox. (c–e) Venn diagram of shared downregulated genes (log₂FC < −1, Padj < 0.05) (c), shared upregulated genes (log₂FC > 2, Padj < 0.01) (d), and shared upregulated genes (log₂FC > 1, Padj < 0.05) (e) between KT;Stag2^flox/KT and KT;H11^LSL-Cas9 sg^Paxip1/KT;H11^LSL-Cas9 sgInert. (f and g) Gene expression (TPM) for Nkx2-1 (f) and Sftpc (g) in neoplastic cells from tumors from KT, KT;Stag2^flox, KT;H11^LSL-Cas9 sgInert, and KT;H11^LSL-Cas9 sgPaxip1 in mice. Each dot is an RNA-seq sample, and the bar is the mean. **P value <0.01, *P value <0.1 by unpaired t test (KT and KT;Stag2^flox data are same as Fig. S2). (h) PCA of KT;H11^LSL-Cas9 sgInert and KT;H11^LSL-Cas9 sgPaxip1 tumors processed with ATAC-seq libraries. (i) Differential accessibility across 17,488 significant peaks in KT;H11^LSL-Cas9 sgInert and KT;H11^LSL-Cas9 sgPaxip1 mice (three mice/group). The x-axis represents the log₂mean accessibility per peak and the y-axis represents the log₂FC in accessibility. Colored dots are significant (log₂FC > |1|, FDR < 0.05). Red dots are increased chromatin accessibility in KT;H11^LSL-Cas9 sgPaxip1 accompanied by transcription factor hypergeometric motif enrichment in KT;H11^LSL-Cas9 sgPaxip1, and blue dots are decreased chromatin accessibility in KT;H11^LSL-Cas9 sgPaxip1 accompanied by transcription factor hypergeometric motif enrichment in KT;H11^LSL-Cas9 sgInert. (j) Venn diagram of shared regions of increased chromatin accessibility (log₂FC > 1, Padj < 0.01) between KT;Stag2^flox/KT and KT;H11^LSL-Cas9 sgPaxip1/KT;H11^LSL-Cas9 sgInert. (k and l) Motif sequences and corresponding P values for transcription factors with motif enrichment in regions with increased accessibility in KT;H11^LSL-Cas9 sgPaxip1 (k) and with decreased accessibility in KT;H11^LSL-Cas9 sgPaxip1 (l). (m) Motif sequences and corresponding P values for transcription factors with motif enrichment in regions with decreases accessibility in KT;H11^LSL-Cas9 sgPaxip1 and KT;Stag2^flox. (n) Venn diagram of differentially expressed genes regulated by KT;H11^LSL-Cas9 sgPaxip1/KT;H11^LSL-Cas9 sgInert (|log₂ FC| >1, Padj < 0.05; RNA-seq) versus genes found in differential loops regulated by KT;Stag2^flox/KT (HiC).