Fig. 7 |. Meis/Hox genes are downstream of the KMT2C–DNMT3A epigenetic reprogramming for SCLC metastasis.

a, Venn diagram showing overlapping of the hypomethylated genes in PRM-Met compared to PRM, PRMK compared to PRM and CCLE KMT2C mutant compared to CCLE KMT2C wild type. P values were calculated by a hypergeometric test. b, IGV plots showing the 5mC densities and RNA-seq peaks of the Meis2 gene bodies. c, IGV plots showing the 5mC densities and RNA-seq peaks of the Hoxb5 and Hoxb7 gene bodies. d, Relative expression levels of Meis2, Hoxb2, Hoxb3, Hoxb4, Hoxb5 and Hoxb7 in PRM and PRMK tumor organoids, as measured by real-time quantitative PCR (RT–qPCR). Data are shown as mean ± s.d.; n = 3 mice. Significance was calculated by two-sided Student’s t-test. e, Relative expression levels of Meis2, Hoxb2, Hoxb3, Hoxb5, Hoxb7 and Hoxb9 in PRM tumor organoids with sgScr and sgDnmt3a, as measured by RT–qPCR; n = 3 mice. f, Relative expression of Meis2, Hoxb5 and Hoxb7 in PRMK organoids with vector or Dnmt3a overexpression, as measured by RT–qPCR. Data are shown as mean ± s.d.; n = 3 organoids. Significance was calculated by two-sided Student’s t-test. g, Percentages of the sgScr and sgMeis2 PRMK SCLC organoids with axon-like protrusions (left) and the number of total sgScr and sgMeis2 PRMK organoids (right). Data are shown as mean ± s.d.; n = 4. Significance was calculated by two-sided Student’s t-test. h, Luciferase fluorescence signal intensities of mice with sgScr or sgMeis2 PRMK SCLC. Data are shown as mean ± s.e.m.; n = 4 mice. Significance was calculated by two-sided Student’s t-test. i, Percentages of sgScr and sgMeis2 PRMK mice with the indicated number of metastases. j, Gene set enrichment analysis showing negative enrichment of the epithelial–mesenchymal transition gene signature in sgMeis2 PRMK cells compared to those with sgScr; *P < 0.05, **P < 0.01, ***P < 0.001; NeS, normalized enrichment score; FDR, false discovery rate.