Functional inactivation (by mutation) of the cystic fibrosis transmembrane conductance regulator (CFTR), a small conductance, cAMP activated chloride ion channel, leads to developmental defects that cause male infertility in humans. The mechanism by which inactivation of the CFTR gene causes infertility is poorly understood but is believed to be due in part to malformations or pathological changes in the male genital duct system. The goals of the proposed research are to decipher the transcriptional networks that regulate luminal environment in the epididymis, by building on our current understanding of the mechanisms regulating expression of the CFTR gene. Mutations in CFTR cause the devastating inherited disorder cystic fibrosis (CF). The CFTR channel makes an essential contribution to ion transport and the luminal environment in the epididymis and its loss causes obstruction and/or loss of the male genital ducts and subsequent infertility. The epididymis forms the proximal part of the excretory duct system of the male reproductive tract and is a complex organ that secretes and absorbs ions, water and inorganic solutes. Critically, it provides the correct luminal environment for normal sperm maturation. In normal epididymis the luminal environment is established and maintained through the functional cooperation of multiple ion channels, ion exchangers, solute carriers and transporters, though the mechanisms that coordinate the expression of these genes has not been well studied. In the first specific aim we will determine how modifications in the chromatin structure of the CFTR locus control its expression in the epididymis. We will evaluate the cis-acting enhancers and insulator elements that likely establish the looped conformation of the active locus and determine how trans-acting factors such as CTCF and cohesin influence this spatial organization. Moreover, we will investigate mechanisms and DNA- binding proteins that may suppress gene expression in cells where CFTR is less active or inactive. Experiments in the second specific aim will determine the transcriptional pathways that coordinate expression of ion channels, ion exchangers, transporters and solute carriers that interact with CFTR in the epididymis epithelium to establish and maintain the luminal environment. We will use a genome-wide approach (DNase- seq) to identify the cis-acting regulatory elements for genes encoding the proteins that contribute to ion and solute transport across the epididymal epithelium. Following mapping of these elements we will use combined bioinformatic and experimental approaches to identify the trans-acting factors that mediate the coordinated regulation of gene expression. Successful conduct of these studies will provide unique translational opportunities to modify male fertility. In disease states we may be able to reinstate the normal epididymal luminal environment and thereby restore fertility. Through modulation of this environment we may also be able to inhibit normal sperm maturation and thereby develop novel methods of birth control.
Functional inactivation (by mutation) of the cystic fibrosis transmembrane conductance regulator (CFTR), a small conductance, cAMP activated chloride ion channel, leads to developmental defects in the genital duct system that cause male infertility in humans. The goals of the proposed research are to decipher the transcriptional networks that regulate luminal environment in the genital ducts, by building on our current understanding of the mechanisms regulating expression of the CFTR gene. Successful conduct of these studies will provide unique translational opportunities to modify male fertility. In infertile disease states we may be able to reinstate the normal epididymal luminal environment and thereby restore fertility. Modulation of this environment may provide ways to inhibit normal sperm maturation and thereby develop novel methods of birth control.
| Strug, Lisa J; Stephenson, Anne L; Panjwani, Naim et al. (2018) Recent advances in developing therapeutics for cystic fibrosis. Hum Mol Genet 27:R173-R186 |
| Yang, Rui; Browne, James A; Eggener, Scott E et al. (2018) A novel transcriptional network for the androgen receptor in human epididymis epithelial cells. Mol Hum Reprod 24:433-443 |
| Gillen, Austin E; Yang, Rui; Cotton, Calvin U et al. (2018) Molecular characterization of gene regulatory networks in primary human tracheal and bronchial epithelial cells. J Cyst Fibros 17:444-453 |
| Browne, James A; Leir, Shih-Hsing; Eggener, Scott E et al. (2018) Region-specific innate antiviral responses of the human epididymis. Mol Cell Endocrinol 473:72-78 |
| Mutolo, Michael J; Leir, Shih-Hsing; Fossum, Sara L et al. (2018) A transcription factor network represses CFTR gene expression in airway epithelial cells. Biochem J 475:1323-1334 |
| Browne, James A; Leir, Shih-Hsing; Eggener, Scott E et al. (2018) Region-specific microRNA signatures in the human epididymis. Asian J Androl 20:539-544 |
| Fossum, Sara L; Mutolo, Michael J; Tugores, Antonio et al. (2017) Ets homologous factor (EHF) has critical roles in epithelial dysfunction in airway disease. J Biol Chem 292:10938-10949 |
| Yang, Rui; Kerschner, Jenny L; Harris, Ann (2016) Hepatocyte nuclear factor 1 coordinates multiple processes in a model of intestinal epithelial cell function. Biochim Biophys Acta 1859:591-8 |
| Browne, James A; Yang, Rui; Leir, Shih-Hsing et al. (2016) Expression profiles of human epididymis epithelial cells reveal the functional diversity of caput, corpus and cauda regions. Mol Hum Reprod 22:69-82 |
| Browne, James A; Yang, Rui; Eggener, Scott E et al. (2016) HNF1 regulates critical processes in the human epididymis epithelium. Mol Cell Endocrinol 425:94-102 |
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