Figure 6.
PAXIP1 and STAG2-cohesin mechanisms of tumor suppression are conserved. (a) Schematic of tumor initiation with Lenti-sgPaxip1/Cre or Lenti-sgInert/Cre in KT;H11LSL-Cas9 mice (three to four mice/group). Mice grew tumors for 15 wk. Outline of tumor cell sorting and sample preparation for bulk RNA-seq and bulk ATAC-seq. (b) Upregulated and downregulated genes (n = 540 genes) in KT;H11LSL-Cas9 sgInert relative to KT;H11LSL-Cas9 sgPaxip1 tumors (|log2FC| > 1, Padj < 0.01). (c) Positive correlation between KT;Stag2flox/KT (log2FC) and KT;H11LSL-Cas9 sgPaxip1/KT;H11LSL-Cas9 sgInert (log2FC). Each dot is a gene. Dots |log2FC| > 1, Padj < 0.05 in both are maroon, dots |log2FC| > 1, Padj < 0.05 in KT;H11LSL-Cas9 sgPaxip1/KT;H11LSL-Cas9 only are pink, and dots |log2FC| > 1, Padj < 0.05 in KT;Stag2flox/KT are dark blue. Dots |log2FC| > 1, Padj < 0.05 in neither are grey. (d) Downregulated PAXIP1 gene signature enrichment in rank-ordered gene list for KT versus KT;Stag2flox. (e) Venn diagram of shared downregulated genes (log2FC < −2, Padj < 0.01) between KT;Stag2flox/KT and KT;H11LSL-Cas9 sgPaxip1/KT;H11LSL-Cas9 sgInert. (f) GO term gene count analysis with ClusterProfiler and EMBL-EBI GO:term category analysis established from conserved downregulated pathways between KT;Stag2flox/KT and KT;H11LSL-Cas9 sgPaxip1/KT;H11LSL-Cas9 sgInert. (g) Venn diagram of shared regions of decreased chromatin accessibility (log2FC < −1, Padj < 0.01) between KT;Stag2flox/KT and KT;H11LSL-Cas9 sgPaxip1/KT;H11LSL-Cas9 sgInert. (h) Accessibility z-score for regions with significantly different accessibility in both KT;Stag2flox/KT and KT;H11LSL-Cas9 sgPaxip1/KT;H11LSL-Cas9 sgInert ATAC-seq samples (|log2 FC| > 1, Padj < 0.01) that are also associated with genes with significantly different expression in both KT;Stag2flox/KT and KT;H11LSL-Cas9 sgPaxip1/KT;H11LSL-Cas9 sgInert neoplastic cells (|log2 FC| > 1, Padj < 0.01). Each row is a differentially accessible region. (i) Enrichment for regions with significant decreased accessibility in KT;Stag2flox/KT (|log2FC| > 1, Padj < 0.01) samples associated with genes with significantly decreased expression in both KT;Stag2flox/KT and KT;H11LSL-Cas9 sgPaxip1/KT;H11LSL-Cas9 sgInert neoplastic cells (log2FC < −1, Padj < 0.01). Changes in accessibility and expression in KT;Stag2flox/KT is shown. Each dot is a differentially accessible region. (j) Model of lung tumor suppression regulated by STAG2-cohesin-PAXIP1/PAGR1 axis.

PAXIP1 and STAG2-cohesin mechanisms of tumor suppression are conserved. (a) Schematic of tumor initiation with Lenti-sgPaxip1/Cre or Lenti-sgInert/Cre in KT;H11LSL-Cas9 mice (three to four mice/group). Mice grew tumors for 15 wk. Outline of tumor cell sorting and sample preparation for bulk RNA-seq and bulk ATAC-seq. (b) Upregulated and downregulated genes (n = 540 genes) in KT;H11LSL-Cas9 sgInert relative to KT;H11LSL-Cas9 sgPaxip1 tumors (|log2FC| > 1, Padj < 0.01). (c) Positive correlation between KT;Stag2flox/KT (log2FC) and KT;H11LSL-Cas9 sgPaxip1/KT;H11LSL-Cas9 sgInert (log2FC). Each dot is a gene. Dots |log2FC| > 1, Padj < 0.05 in both are maroon, dots |log2FC| > 1, Padj < 0.05 in KT;H11LSL-Cas9 sgPaxip1/KT;H11LSL-Cas9 only are pink, and dots |log2FC| > 1, Padj < 0.05 in KT;Stag2flox/KT are dark blue. Dots |log2FC| > 1, Padj < 0.05 in neither are grey. (d) Downregulated PAXIP1 gene signature enrichment in rank-ordered gene list for KT versus KT;Stag2flox. (e) Venn diagram of shared downregulated genes (log2FC < −2, Padj < 0.01) between KT;Stag2flox/KT and KT;H11LSL-Cas9 sgPaxip1/KT;H11LSL-Cas9 sgInert. (f) GO term gene count analysis with ClusterProfiler and EMBL-EBI GO:term category analysis established from conserved downregulated pathways between KT;Stag2flox/KT and KT;H11LSL-Cas9 sgPaxip1/KT;H11LSL-Cas9 sgInert. (g) Venn diagram of shared regions of decreased chromatin accessibility (log2FC < −1, Padj < 0.01) between KT;Stag2flox/KT and KT;H11LSL-Cas9 sgPaxip1/KT;H11LSL-Cas9 sgInert. (h) Accessibility z-score for regions with significantly different accessibility in both KT;Stag2flox/KT and KT;H11LSL-Cas9 sgPaxip1/KT;H11LSL-Cas9 sgInert ATAC-seq samples (|log2 FC| > 1, Padj < 0.01) that are also associated with genes with significantly different expression in both KT;Stag2flox/KT and KT;H11LSL-Cas9 sgPaxip1/KT;H11LSL-Cas9 sgInert neoplastic cells (|log2 FC| > 1, Padj < 0.01). Each row is a differentially accessible region. (i) Enrichment for regions with significant decreased accessibility in KT;Stag2flox/KT (|log2FC| > 1, Padj < 0.01) samples associated with genes with significantly decreased expression in both KT;Stag2flox/KT and KT;H11LSL-Cas9 sgPaxip1/KT;H11LSL-Cas9 sgInert neoplastic cells (log2FC < −1, Padj < 0.01). Changes in accessibility and expression in KT;Stag2flox/KT is shown. Each dot is a differentially accessible region. (j) Model of lung tumor suppression regulated by STAG2-cohesin-PAXIP1/PAGR1 axis.

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