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Simple Summary  Tissue heterogeneity is one of the major problems in cancer genomics. Thus, we developed and conducted an RNA-Seq and ChIP-Seq integrative analysis of clinical lung tissue samples with the isolation of specific cell populations using laser-microdissection microscopy (LMD). The transcriptomic profile was successfully captured and somatically altered regions marked by histone H3 lysine 4 trimethylation (H3K4me3) were identified in lung cancer. We also observed the differential expressions of cancer-related genes near the altered proximal H3K4me3 regions, while altered distal H3K4me3 regions were overlapped with enhancer activity annotations of cancer regulatory genes. Additionally, proximal tumor-gained promoters were associated with the core components of polycomb repressive complex 2. Our study demonstrates the practical workflow of using LMD on clinical samples for integrative analyses, which improves the overall understanding of genetic and epigenetic dysregulation of malignancy.    Abstract  Our previous integrative study in gastric cancer discovered cryptic promoter activation events that drive the expression of important developmental genes. However, it was unclear if such cancer-associated epigenetic changes occurred in cancer cells or other cell types in bulk tissue samples. An integrative analysis consisting of RNA-Seq and H3K4me3 ChIP-Seq was used. This workflow was applied to a set of matched normal lung tissues and non-small cell lung cancer (NSCLC) tissues, for which the stroma and tumor cell parts could be isolated by laser-microdissection microscopy (LMD). RNA-Seq analysis showed subtype-specific differential expressed genes and enriched pathways in NSCLC. ChIP-Seq analysis results suggested that the proximal altered H3K4me3 regions were located at differentially expressed genes involved in cancer-related pathways, while altered distal H3K4me3 regions were annotated with enhancer activity of cancer regulatory genes. Interestingly, integration with ENCODE data revealed that proximal tumor-gained promoters were associated with EZH2 and SUZ12 occupancies, which are the core components of polycomb repressive complex 2 (PRC2). This study used LMD on clinical samples for an integrative analysis to overcome the tissue heterogeneity problem in cancer research. The results also contribute to the overall understanding of genetic and epigenetic dysregulation of lung malignancy.

Integrative RNA-Seq and H3 Trimethylation ChIP-Seq Analysis of Human Lung Cancer Cells Isolated by Laser-Microdissection