The goal of this project is to investigate the role of chromatin modifications and DMA methylation in activation or silencing of gene expression during initiation of lung development. Chromatin modifications and DNA methylation in conjunction with DNA binding factors regulate transcription to achieve cell specific gene expression. These mechanisms play a defined role in developmental programs, and have been shown to be involved in the establishment of the specific cell lineages that will give rise to various organs, including foregut derivatives such as the liver. Little is known about how these mechanisms influence gene expression in the developing lung. In a microarray analysis of the developing foregut carried during the previous period of this Program Project, we identified significant changes in the expression of genes associated with chromatin remodeling and DNA methylation, coincident with the formation of the lung primordium. The known important role of chromatin remodeling in cell fate decisions and differentiation led us to hypothesize that chromatin remodeling and DNA methylation play a regulatory role in initiation of lung development by establishing spatial and temporal patterns of gene expression in the embryonic foregut. Thus we propose to: 1) identify changes in epigenetic modifications of selected lung gene promoters during initiation of lung development in vivo and in cultured ES cells, 2) search for targets of activating chromatin remodeling complexes in embryonic lung cells, 3) analyze the function of chromatin remodeling genes and DNA methylation on the transcriptional activity of lung promoters in cells, and in wild type and genetically modified lungs. The proposed studies include the characterization of chromatin modifications of lung gene promoters by chromatin immunoprecipitation, DNA methylation and chromatin accessibility analyses in vitro and in vivo, a global analysis of new targets of epigenetic gene activation, and the functional evaluation of chromatin modification genes in lung gene development using foregut cultures and genetically modified mice. Our findings will increase the knowledge of how the early patterns of lung expression are regulated in vivo and in ES cells.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Program Projects (P01)
Project #
5P01HL047049-20
Application #
8374958
Study Section
Heart, Lung, and Blood Initial Review Group (HLBP)
Project Start
Project End
2014-01-31
Budget Start
2012-02-01
Budget End
2013-01-31
Support Year
20
Fiscal Year
2012
Total Cost
$336,604
Indirect Cost
$126,663
Name
Boston University
Department
Type
DUNS #
604483045
City
Boston
State
MA
Country
United States
Zip Code
02118
Cushing, Leah; Costinean, Stefan; Xu, Wei et al. (2015) Disruption of miR-29 Leads to Aberrant Differentiation of Smooth Muscle Cells Selectively Associated with Distal Lung Vasculature. PLoS Genet 11:e1005238
Cushing, Leah; Jiang, Zhihua; Kuang, Pingping et al. (2015) The roles of microRNAs and protein components of the microRNA pathway in lung development and diseases. Am J Respir Cell Mol Biol 52:397-408
Mori, Munemasa; Mahoney, John E; Stupnikov, Maria R et al. (2015) Notch3-Jagged signaling controls the pool of undifferentiated airway progenitors. Development 142:258-67
Tagne, Jean-Bosco; Mohtar, Omar R; Campbell, Joshua D et al. (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
Guha, Arjun; Vasconcelos, Michelle; Zhao, Rui et al. (2014) Analysis of Notch signaling-dependent gene expression in developing airways reveals diversity of Clara cells. PLoS One 9:e88848
Mahoney, John E; Mori, Munemasa; Szymaniak, Aleksander D et al. (2014) The hippo pathway effector Yap controls patterning and differentiation of airway epithelial progenitors. Dev Cell 30:137-50
Jiang, Zhihua; Cushing, Leah; Ai, Xingbin et al. (2014) miR-326 is downstream of Sonic hedgehog signaling and regulates the expression of Gli2 and smoothened. Am J Respir Cell Mol Biol 51:273-83
Jean, Jyh-Chang; George, Elizabeth; Kaestner, Klaus H et al. (2013) Transcription factor Klf4, induced in the lung by oxygen at birth, regulates perinatal fibroblast and myofibroblast differentiation. PLoS One 8:e54806
Tagne, Jean-Bosco; Gupta, Sumeet; Gower, Adam C et al. (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:e29907
Sommer, Cesar A; Christodoulou, Constantina; Gianotti-Sommer, Andreia et al. (2012) Residual expression of reprogramming factors affects the transcriptional program and epigenetic signatures of induced pluripotent stem cells. PLoS One 7:e51711

Showing the most recent 10 out of 92 publications