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Ann Harris
Professor/Vice Chair of Research
Department of Genetics
School of Medicine
Case Western Reserve University
Biomedical Research Building 724
2109 Adelbert Road
Cleveland, Ohio 44106-4955
Tel: (216) 368-6651
Fax: (216) 368-3432
E-mail: ann.harris@case.edu


About Ann Harris


Research

The main research focus in the laboratory is on transcriptional networks that coordinate gene expression in human epithelia. The unique properties of the epithelia lining the respiratory, digestive and reproductive systems are determined by transcription factors that establish and maintain the specific program of differentiation. Our interest in this topic developed through elucidation of the regulatory mechanisms for a single gene, the cystic fibrosis transmembrane conductance regulator (CFTR) gene, which when mutated causes the devastating inherited disease cystic fibrosis. CFTR encodes a chloride ion channel that is critical to the function of many epithelia. The CFTR gene encompasses nearly 200 kb of genomic DNA which is isolated within a single transcriptional domain. Within this, distal cis-acting regulatory elements are brought into close proximity with the gene promoter to modulate its activity. We identified many of the cell-type-selective transcription factors (TFs) that bind to these cis-elements. In recent work we revealed the targets for several of the key TFs genome wide, using ChIP-seq together with open chromatin mapping by DNase-seq. These studies enabled us to start determining the transcriptional networks that control epithelial cell identity and how individual TFs contribute to this coordinated gene expression. In a closely related project we are investigating the molecular basis of genetic elements affecting lung disease severity in CF. A genome-wide association study (GWAS) performed by others demonstrated that SNPs at Chr11:p13 tracked with this phenotype. These SNPs lie in an intergenic region that is flanked on one side by two epithelial-selective TFs and on the other by a gene involved in apoptosis. We are using a range of state of the art techniques to determine how this region of chromosome 11 impacts lung disease. Additional research interests in the laboratory include epithelial reprogramming in pancreas cancer.


Selected Publications

Yang R, Kerschner JL, Gosalia N, Neems D, Gorsic LK, Safi A, Crawford GE, Kosak ST, Leir SH, Harris A (2016)
Differential contribution of cis-regulatory elements to higher order chromatin structure and expression of the CFTR locus.
Nucleic Acids Res;44(7):3082-94
See PubMed abstract

Browne JA, Yang R, Eggener SE, Leir SH, Harris A (2016)
HNF1 regulates critical processes in the human epididymis epithelium.
Mol Cell Endocrinol;425:94-102
See PubMed abstract

Yang R, Kerschner JL, Harris A (2016)
Hepatocyte nuclear factor 1 coordinates multiple processes in a model of intestinal epithelial cell function.
Biochim Biophys Acta;1859(4):591-8
See PubMed abstract

Browne JA, Yang R, Leir SH, Eggener SE, Harris A (2016)
Expression profiles of human epididymis epithelial cells reveal the functional diversity of caput, corpus and cauda regions.
Mol Hum Reprod;22(2):69-82
See PubMed abstract

Stolzenburg LR, Wachtel S, Dang H, Harris A (2016)
miR-1343 attenuates pathways of fibrosis by targeting the TGF-β receptors.
Biochem J;473(3):245-56
See PubMed abstract

Gosalia N, Yang R, Kerschner JL, Harris A (2015)
FOXA2 regulates a network of genes involved in critical functions of human intestinal epithelial cells.
Physiol Genomics;47(7):290-7
See PubMed abstract

Cai Z, Palmai-Pallag T, Khuituan P, Mutolo MJ, Boinot C, Liu B, Scott-Ward TS, Callebaut I, Harris A, Sheppard DN (2015)
Impact of the F508del mutation on ovine CFTR, a Cl- channel with enhanced conductance and ATP-dependent gating.
J Physiol;593(11):2427-46
See PubMed abstract

Leir SH, Browne JA, Eggener SE, Harris A (2015)
Characterization of primary cultures of adult human epididymis epithelial cells.
Fertil Steril;103(3):647-54.e1
See PubMed abstract

Zhang Z, Leir SH, Harris A (2015)
Oxidative stress regulates CFTR gene expression in human airway epithelial cells through a distal antioxidant response element.
Am J Respir Cell Mol Biol;52(3):387-96
See PubMed abstract

Gosalia N, Harris A (2015)
Chromatin Dynamics in the Regulation of CFTR Expression.
Genes (Basel);6(3):543-58
See PubMed abstract

Fossum SL, Mutolo MJ, Yang R, Dang H, O'Neal WK, Knowles MR, Leir SH, Harris A (2014)
Ets homologous factor regulates pathways controlling response to injury in airway epithelial cells.
Nucleic Acids Res;42(22):13588-98
See PubMed abstract

Browne JA, Yang R, Song L, Crawford GE, Leir SH, Harris A (2014)
Open chromatin mapping identifies transcriptional networks regulating human epididymis epithelial function.
Mol Hum Reprod;20(12):1198-207
See PubMed abstract

Gosalia N, Neems D, Kerschner JL, Kosak ST, Harris A (2014)
Architectural proteins CTCF and cohesin have distinct roles in modulating the higher order structure and expression of the CFTR locus.
Nucleic Acids Res;42(15):9612-22
See PubMed abstract

Kerschner JL, Gosalia N, Leir SH, Harris A (2014)
Chromatin remodeling mediated by the FOXA1/A2 transcription factors activates CFTR expression in intestinal epithelial cells.
Epigenetics;9(4):557-65
See PubMed abstract

Browne JA, Harris A, Leir SH (2014)
An optimized protocol for isolating primary epithelial cell chromatin for ChIP.
PLoS One;9(6):e100099
See PubMed abstract

Zhang Z, Leir SH, Harris A (2013)
Immune mediators regulate CFTR expression through a bifunctional airway-selective enhancer.
Mol Cell Biol;33(15):2843-53
See PubMed abstract

Yigit E, Bischof JM, Zhang Z, Ott CJ, Kerschner JL, Leir SH, Buitrago-Delgado E, Zhang Q, Wang JP, Widom J, Harris A (2013)
Nucleosome mapping across the CFTR locus identifies novel regulatory factors.
Nucleic Acids Res;41(5):2857-68
See PubMed abstract

Gosalia N, Leir SH, Harris A (2013)
Coordinate regulation of the gel-forming mucin genes at chromosome 11p15.5.
J Biol Chem;288(9):6717-25
See PubMed abstract

Clementz AG, Mutolo MJ, Leir SH, Morris KJ, Kucybala K, Harris H, Harris A (2013)
Collagen XV inhibits epithelial to mesenchymal transition in pancreatic adenocarcinoma cells.
PLoS One;8(8):e72250
See PubMed abstract

Kerschner JL, Harris A (2012)
Transcriptional networks driving enhancer function in the CFTR gene.
Biochem J;446(2):203-12
See PubMed abstract

Zhang Z, Ott CJ, Lewandowska MA, Leir SH, Harris A (2012)
Molecular mechanisms controlling CFTR gene expression in the airway.
J Cell Mol Med;16(6):1321-30
See PubMed abstract

Mutolo MJ, Morris KJ, Leir SH, Caffrey TC, Lewandowska MA, Hollingsworth MA, Harris A (2012)
Tumor suppression by collagen XV is independent of the restin domain.
Matrix Biol;31(5):285-9
See PubMed abstract

Bischof JM, Ott CJ, Leir SH, Gosalia N, Song L, London D, Furey TS, Cotton CU, Crawford GE, Harris A (2012)
A genome-wide analysis of open chromatin in human tracheal epithelial cells reveals novel candidate regulatory elements for lung function.
Thorax;67(5):385-91
See PubMed abstract

Gillen AE, Harris A (2012)
Transcriptional regulation of CFTR gene expression.
Front Biosci (Elite Ed);4:587-92
See PubMed abstract

Ott CJ, Bischof JM, Unti KM, Gillen AE, Leir SH, Harris A (2012)
Nucleosome occupancy reveals regulatory elements of the CFTR promoter.
Nucleic Acids Res;40(2):625-37
See PubMed abstract

Leir SH, Harris A (2011)
MUC6 mucin expression inhibits tumor cell invasion.
Exp Cell Res;317(17):2408-19
See PubMed abstract

Gillen AE, Harris A (2011)
The role of CTCF in coordinating the expression of single gene loci.
Biochem Cell Biol;89(5):489-94
See PubMed abstract

Gillen AE, Gosalia N, Leir SH, Harris A (2011)
MicroRNA regulation of expression of the cystic fibrosis transmembrane conductance regulator gene.
Biochem J;438(1):25-32
See PubMed abstract

Ott CJ, Harris A (2007)
Genomic approaches for the discovery of CFTR regulatory elements.
Transcription;2(1):23-7
See PubMed abstract