Biomedical Sciences ETDs

Xiaobo Sun

Publication Date

7-1-2009

Abstract

Motile cilia of the mammalian airway play an essential role in innate defense. The coordinated transcriptional regulation of cilial axoneme genes remains to be elucidated. Transcription factor FOXJ1 has been shown to be important in ciliogenesis; however, direct transactivation of cilia genes by FOXJ1 has not been reported. Using a combined bioinformatics and experimental approach, here, we show a transcriptional network for cilia gene expression. FOXJ1 can directly transactivate endogenous cilia genes such as ENKURIN, EFHC2, IFT57, RIBC2 and ROPN1L in human bronchial epithelial cells (HBEC). FOXJ1 transactivation is localized to the proximal end of the 5 flanking region of ENKURIN and EFHC2 promoters. However, FOXJ1 failed to transactivate HSPA1A and MNS1, two other cilia genes, indicating there are other transcription factor(s)involved in the ciliogenesis. Motif discovery analysis indicates ETS and RFX binding sites located in promoters of several cilia genes (IFT57, HSPA1A, MNS1, RIBC2 and ROPN1L). QRT-PCR indicates 5 of 27 human ETS transcription factors members (ETV1, ETV5, SPDEF, SPIC and ESE1) and 4 of 7 RFX transcription factors (RFX1, RFX2, RFX5 and RFXANK) are regulated coincidently with the differentiation of human bronchial epithelial cells and the appearance of cilia, suggesting these transcription factors are involved in gene regulations during lung airway epithelial ciliogenesis. ETS family members ESE1 and ETV1 both can transactivate endogenous EFHC2 and ENKURIN while SPIC represses EFHC2. An RFX family member RFX1 transactivates endogenous ENKURIN, HSPA1A, ROPN1L, and RFX5 transactivates EFHC2, HSPA1A and RIBC2. Furthermore, another transcription factor, GATA2, transactivates endogenous ENKURIN and EFHC2, and its transactivation also locates in the proximal end of the 5' flanking region of ENKURIN and EFHC2 promoters. Our work defines a transcriptional network that regulates expression of cilia genes during airway epithelial differentiation and highlights the importance of multiple transcription factors in ciliogenesis.

Keywords

Transcriptional Regulation, Lung Airway Epithelium, Cilia, Ciliogenesis

Sponsors

Lovelace Respiratory Research Institute

Document Type

Thesis

Language

English

Degree Name

Biomedical Sciences

Level of Degree

Masters

Department Name

Biomedical Sciences Graduate Program

First Committee Member (Chair)

Hjelle, Brian

Second Committee Member

Harrod, Kevin

Third Committee Member

Rubin, Robert

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