Ramirez Research

Tagne JB, Mohtar OR, Campbell JD, Lakshminarayanan M, Huang J, Hinds AC, Lu J, Ramirez MI. (2015) Transcription factor and microRNA interactions in lung cells: an inhibitory link between NK2 homeobox 1, miR-200c and the developmental and oncogenic factors Nfib and Myb. Respir Res. 16:22

The transcription factor NK2 homeobox 1 (Nkx2-1) plays essential roles in epithelial cell proliferation and differentiation in mouse and human lung development and tumorigenesis. In this work, we identified Nkx2-1-regulated microRNAs (miRNAs) in lung epithelial cells.  We further identified a regulatory link between Nkx2-1, the known tumor suppressor miR-200c, and the developmental and oncogenic transcription factors Nfib and Myb, adding new players to the regulatory mechanisms driven by Nkx2-1 in lung epithelial cells that may have implications in lung development and tumorigenesis.

Tagne JB, Gupta S, Gower AC, Shen SS, Varma S, Lakshminarayanan M, Cao Y, Spira A, Volkert TL, Ramirez MI. (2012) Genome-wide analyses of Nkx2-1 binding to transcriptional target genes uncover novel regulatory patterns conserved in lung development and tumors. PLoS One.7(1):e29907.

We have studied the transcriptional program controlled by NKX2-1 in early and late development and in lung cancer. We discovered a preferential role for NKX2-1 in the regulation of proliferation-related genes in early development including E2F3, Cyclin B1 and B2, and Met. Developmental target genes in lung cancer showed correlated expression to the levels of NKX2-1 in human lung tumor data sets uncovering regulatory networks in normal development that when altered may lead to related developmental and adult lung diseases.

Varma S, Cao Y, Tagne JB, Lakshminarayanan M, Li J, Friedman TB, Morell RJ, Warburton D, Kotton DN, Ramirez MI. (2012) The transcription factors Grainyhead-like 2 and NK2-homeobox 1 form a regulatory loop that coordinates lung epithelial cell morphogenesis and differentiation. J Biol Chem. 287(44):37282-95.\

In this work, we have identified genes regulated by Grhl2 in lung epithelial cells and provided evidence for a novel positive transcriptional feedback loop between Grhl2 and the homeobox transcription factor Nkx2-1 in embryonic lung. We showed that GRHL2 regulates cell-cell interaction genes, collective cell migration, and Nkx2-1 transcription. The Grhl2- and Nkx2-1-positive transcriptional loop likely coordinates morphogenesis and differentiation of lung epithelial cells, reinforcing normal lung epithelial cell identity.

Cao Y, Vo T, Millien G, Tagne JB, Kotton D, Mason RJ, Williams MC, Ramirez MI. (2010) Epigenetic mechanisms modulate thyroid transcription factor 1-mediated transcription of the surfactant protein B gene. J Biol Chem. 285(3):2152-64.

We have characterized the cooperation of DNA methylation mechanisms and the chromatin modifying ATPase Brg1 on the Nkx2-1-mediated transcription of the mouse Sftpb gene.  

Millien G, Beane J, Lenburg M, Tsao PN, Lu J, Spira A, Ramirez MI. (2008) Characterization of the mid-foregut transcriptome identifies genes regulated during lung bud induction. Gene Expr Patterns 8(2):124-39..

In this study, we characterized the transcriptome of the mid-region of the mouse foregut during the period between lung specification of foregut cells and appearance of the initial lung buds.    We identified significant changes in expression level of genes associated with chromatin remodeling and DNA methylation, coincident with formation of the lung primordium. We further studied these factors since they likely activate the developmental program that sustains lung formation.