Global Regulatory DNA Potentiation by SMARCA4 Propagates to Selective Gene Expression Programs via Domain-Level Remodeling.

The human genome encodes millions of regulatory elements, of which only a small fraction are active within a given cell type. Little is known about the global impact of chromatin remodelers on regulatory DNA landscapes and how this translates to gene expression. We use precision genome engineering to reawaken homozygously inactivated SMARCA4, a central ATPase of the human SWI/SNF chromatin remodeling complex, in lung adenocarcinoma cells. Here, we combine DNase I hypersensitivity, histone modification, and transcriptional profiling to show that SMARCA4 dramatically increases both the number and magnitude of accessible chromatin sites genome-wide, chiefly by unmasking sites of low regulatory factor occupancy. By contrast, transcriptional changes are concentrated within well-demarcated remodeling domains wherein expression of specific genes is gated by both distal element activation and promoter chromatin configuration. Our results provide a perspective on how global chromatin remodeling activity is translated to gene expression via regulatory DNA.

Corrigendum: Positively selected enhancer elements endow osteosarcoma cells with metastatic competence.

This corrects the article DOI: 10.1038/nm.4475.

Positively selected enhancer elements endow osteosarcoma cells with metastatic competence.

Metastasis results from a complex set of traits acquired by tumor cells, distinct from those necessary for tumorigenesis. Here, we investigate the contribution of enhancer elements to the metastatic phenotype of osteosarcoma. Through epigenomic profiling, we identify substantial differences in enhancer activity between primary and metastatic human tumors and between near isogenic pairs of highly lung metastatic and nonmetastatic osteosarcoma cell lines. We term these regions metastatic variant enhancer loci (Met-VELs). Met-VELs drive coordinated waves of gene expression during metastatic colonization of the lung. Met-VELs cluster nonrandomly in the genome, indicating that activity of these enhancers and expression of their associated gene targets are positively selected. As evidence of this causal association, osteosarcoma lung metastasis is inhibited by global interruptions of Met-VEL-associated gene expression via pharmacologic BET inhibition, by knockdown of AP-1 transcription factors that occupy Met-VELs, and by knockdown or functional inhibition of individual genes activated by Met-VELs, such as that encoding coagulation factor III/tissue factor (F3). We further show that genetic deletion of a single Met-VEL at the F3 locus blocks metastatic cell outgrowth in the lung. These findings indicate that Met-VELs and the genes they regulate play a functional role in metastasis and may be suitable targets for antimetastatic therapies.