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In other epithelia, there is evidence that transcription factors of the evolutionarily conserved grainyheadlike (GRHL) family play key roles in coordinating multiple cellular processes required for epithelial morphogenesis, differentiation, remodeling, and repair. However, only a few target genes have been identified, and little is known about GRHL function in the adult lung. Here we focus on the role of GRHL2 in primary human bronchial epithelial cells, both as undifferentiated progenitors and as they differentiate in air\u2013liquid interface culture into an organized mucociliary epithelium with transepithelial resistance. Using a dominant-negative protein or shRNA to inhibit GRHL2, we follow changes in epithelial phenotype and gene transcription using RNA sequencing or microarray analysis. We identify several hundreds of genes that are directly or indirectly regulated by GRHL2 in both undifferentiated cells and air\u2013liquid interface cultures. Using ChIP sequencing to map sites of GRHL2 binding in the basal cells, we identify 7,687 potential primary targets and confirm that GRHL2 binding is strongly enriched near GRHL2-regulated genes. Taken together, the results support the hypothesis that GRHL2 plays a key role in regulating many physiological functions of human airway epithelium, including those involving cell morphogenesis, adhesion, and motility.<\/jats:p>","DOI":"10.1073\/pnas.1307589110","type":"journal-article","created":{"date-parts":[[2013,5,21]],"date-time":"2013-05-21T01:03:59Z","timestamp":1369098239000},"page":"9356-9361","update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":73,"title":["Evidence for multiple roles for grainyhead-like 2 in the establishment and maintenance of human mucociliary airway epithelium"],"prefix":"10.1073","volume":"110","author":[{"given":"Xia","family":"Gao","sequence":"first","affiliation":[{"name":"Department of Cell Biology,"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christopher M.","family":"Vockley","sequence":"additional","affiliation":[{"name":"Department of Cell Biology,"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Florencia","family":"Pauli","sequence":"additional","affiliation":[{"name":"HudsonAlpha Institute for Biotechnology, Huntsville, AL 35806; and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kimberly M.","family":"Newberry","sequence":"additional","affiliation":[{"name":"HudsonAlpha Institute for Biotechnology, Huntsville, AL 35806; and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yan","family":"Xue","sequence":"additional","affiliation":[{"name":"Department of Cell Biology,"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Scott H.","family":"Randell","sequence":"additional","affiliation":[{"name":"Department of Cell Biology and Physiology, University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, NC 27599"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Timothy E.","family":"Reddy","sequence":"additional","affiliation":[{"name":"Department of Biostatistics and Bioinformatics, and"},{"name":"Institute of Genome Sciences and Policy, Duke University, Durham, NC 27710;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Brigid L. 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