Genome-Wide Analyses of Nkx2-1 Binding to Transcriptional Target Genes Uncovers Novel Regulatory Patterns Conserved in Lung Development and Tumors

Researchers Drs. Jean Bosco Tagne and Maria Ramirez along with collaborators from the Pulmonary Center, BU’s CTSI and the Whitehead Institute for Biomedical Research/MIT, provide novel insights into biological processes regulated by the transcription factor Nkx2-1 in different cell contexts, in early and late development, and in cancer. These findings recently appeared in PLoS ONE.

Nkx2-1 regulates lung, thyroid and brain development; and is a lineage survival oncogene and prognostic factor since high levels of NKX2-1 in tumors correlate with better patient prognosis.

Using a genome-wide approach, the researchers located binding of Nkx2-1 to DNA regulatory regions using a method known as ChIP-chip. They uncovered Nkx2-1 regulatory networks in early and late lung development, and a direct function of Nkx2-1 in regulation of proliferation-related genes. They also showed that developmental targets of Nkx2-1 correlate to the endogenous levels of NKX2-1 in more than ten human non-small cell lung carcinoma data sets. Previous genomic associations between human lung cancer subtypes and developing mouse lung indicated that tumors with genomic profiles similar to early lung development correlate to poorer patient’s prognosis while tumors with gene expression profiles similar to more differentiated lung cell phenotypes correlate to better patient’s prognosis.

“The correlations identified in this work provide a rationale to sub-classify NSCLCs based on NKX2-1 and downstream targets expression patterns, and to understand the mechanisms underlying associations to survival,” explained lead author Bosco Tagne, an assistant professor of medicine at BUSM. “These findings are a substantial addition to the development and cancer fields, and an important foundation for further work in regulatory gene networks,” he added.

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