Genome-wide maps of histone modifications in mouse tumor-derived cell lines

Amplification of chromosomal region 8p11-12 is a frequent genetic alteration implicated in the etiology of lung squamous cell carcinoma (LUSC). Here we identify the H3K36 methyltransferase NSD3 (nuclear receptor binding SET domain protein 3), an 8p11-12-localized gene, as a key regulator of LUSC tumorigenesis. We identify NSD3T1232A as an LUSC-associated variant that increases H3K36 dimethylation (H3K36me2) catalytic activity in vitro and in vivo. NSD3T1232A expression in vivo in LUSC mouse models accelerates tumorigenesis and decreases overall survival. Pathologic generation of H3K36me2 by NSD3T1232A rewires the chromatin landscape to promote oncogenic gene expression programming. Together, our work identifies NSD3 as a principal 8p11-12 amplicon-associated oncogenic driver in LUSC and suggests that NSD3-dependency renders LUSC therapeutically vulnerable to BETi. Here we report the application of Cut and Run technology for high-throughput prolifiling of histone modiifcations in mouse tumor-derived cell lines. We found NSD3 loss leads to decrase of histone H3 lysine 36 dimethylation over gene body regions and intergenic regions, while histone H3 lysine 27 trimethylation is increased over these regions. We also reported that NSD3 depletion mainly down-regulates the expression of genes in PI3K-Akt-mTORC1 pathway and Myc targets through total RNA-seq. Overall design: Examination of 2 different histone modifications in mouse tumor-derived cell lines in 2 different conditions