NFIB is necessary and sufficient to remodel chromatin to drive SCLC metastasis.
Major finding: NFIB is necessary and sufficient to remodel chromatin to drive SCLC metastasis.
Mechanism: NFIB enhances chromatin accessibility at distal regulatory elements of prometastatic neuronal genes.
Impact: NFIB induces large-scale chromatin remodeling to promote a stable highly metastatic state.
Metastases in patients with small cell lung cancer (SCLC) hinder treatment and reduce survival, but the mechanisms that drive metastatic progression remain largely unknown. Denny, Yang, and colleagues compared cells from genetically engineered SCLC mouse primary tumors with matched liver metastases to map the chromatin accessibility landscapes using assay for transposase-accessible chromatin using sequencing (ATAC-seq). Among identified differentially accessible regions, approximately 24% were more accessible in the metastases, whereas only 0.5% were more accessible in the primary tumors, indicating that a hyperaccessible chromatin state may be characteristic of SCLC metastases. The differentially accessible regions were largely gene distal in evolutionarily conserved regions of lower gene density, suggesting they might include possible regulatory elements. These regions were enriched for nuclear factor I (NFI) transcription factor binding motifs, and the hyperaccessible samples exhibited genomic amplification of the Nfib locus, which also occurs in 5% to 15% of human primary SCLCs. Consistent with these findings, the majority of invasive or metastatic SCLCs exhibited high expression of NFIB, and single-cell analyses revealed that metastatic cells were mostly homogeneously NFIB-positive, suggesting that NFIB expression is required for metastasis. Transcription factor footprinting showed increased binding at NFI sites in hyperaccessible samples, and differentially accessible regions around NFI sites were more nucleosome-depleted, suggesting that NFIB competes with nucleosomes for DNA binding to create an accessible chromatin state. NFIB expression was both necessary and sufficient to drive chromatin opening at NFIB-sensitive distal regulatory regions and maintain the accessible chromatin state, and to promote metastasis in vivo. Moreover, SCLCs are neuroendocrine tumors, and NFIB promoted the expression of prometastatic genes involved in neuronal function. In addition to implicating NFIB in stabilizing an accessible chromatin state at distal regulatory elements, these findings elucidate an epigenetic mechanism by which chromatin remodeling can promote a stable and highly metastatic state.