Genome-Wide Analyses of Nkx2-1 Binding to Transcriptional Target Genes Uncover Novel Regulatory Patterns Conserved in Lung Development and Tumors
Open Access
- 5 January 2012
- journal article
- research article
- Published by Public Library of Science (PLoS) in PLOS ONE
- Vol. 7 (1), e29907
- https://doi.org/10.1371/journal.pone.0029907
Abstract
The homeodomain transcription factor Nkx2-1 is essential for normal lung development and homeostasis. In lung tumors, it is considered a lineage survival oncogene and prognostic factor depending on its expression levels. The target genes directly bound by Nkx2-1, that could be the primary effectors of its functions in the different cellular contexts where it is expressed, are mostly unknown. In embryonic day 11.5 (E11.5) mouse lung, epithelial cells expressing Nkx2-1 are predominantly expanding, and in E19.5 prenatal lungs, Nkx2-1-expressing cells are predominantly differentiating in preparation for birth. To evaluate Nkx2-1 regulated networks in these two cell contexts, we analyzed genome-wide binding of Nkx2-1 to DNA regulatory regions by chromatin immunoprecipitation followed by tiling array analysis, and intersected these data to expression data sets. We further determined expression patterns of Nkx2-1 developmental target genes in human lung tumors and correlated their expression levels to that of endogenous NKX2-1. In these studies we uncovered differential Nkx2-1 regulated networks in early and late lung development, and a direct function of Nkx2-1 in regulation of the cell cycle by controlling the expression of proliferation-related genes. New targets, validated in Nkx2-1 shRNA transduced cell lines, include E2f3, Cyclin B1, Cyclin B2, and c-Met. Expression levels of Nkx2-1 direct target genes identified in mouse development significantly correlate or anti-correlate to the levels of endogenous NKX2-1 in a dosage-dependent manner in multiple human lung tumor expression data sets, supporting alternative roles for Nkx2-1 as a transcriptional activator or repressor, and direct regulator of cell cycle progression in development and tumors.This publication has 72 references indexed in Scilit:
- Suppression of lung adenocarcinoma progression by Nkx2-1Nature, 2011
- Epigenetic Mechanisms Modulate Thyroid Transcription Factor 1-mediated Transcription of the Surfactant Protein B GeneOnline Journal of Public Health Informatics, 2010
- A Time and a Place for Nkx2-1 in Interneuron Specification and MigrationNeuron, 2008
- The Requirement of Nkx2-1 in the Temporal Specification of Cortical Interneuron SubtypesNeuron, 2008
- Postmitotic Nkx2-1 Controls the Migration of Telencephalic Interneurons by Direct Repression of Guidance ReceptorsNeuron, 2008
- Genomic profiling identifies TITF1 as a lineage-specific oncogene amplified in lung cancerOncogene, 2008
- Characterizing the cancer genome in lung adenocarcinomaNature, 2007
- Oncogenic cooperation and coamplification of developmental transcription factor genes in lung cancerProceedings of the National Academy of Sciences of the United States of America, 2007
- Chromatin immunoprecipitation and microarray-based analysis of protein locationNature Protocols, 2006
- Transcriptional Regulatory Networks in Saccharomyces cerevisiaeScience, 2002