Carolyn J. Mattingly, Ph.D.
Staff Scientist
Mount Desert Island Biological Laboratory
PO Box 35
Old Bar Harbor Rd
Salisbury Cove, ME 04672
207-288-3605
cmattin@mdibl.org
INBRE Research Project
Identification of Novel Regulatory Sequences in ABCB and ABCC Subfamily Genes by Comparative Genomic Analysis
Research Interests
The goal of this project is to identify functionally significant regulatory motifs in noncoding regions of genes from two subfamilies of the ATP Binding Cassette (ABC) superfamily of proteins. The ABC superfamily constitutes one of the most abundant families of transmembrane proteins in both eukaryotes and prokaryotes. These proteins function as transporters, ion channels and receptors and many hydrolyze ATP and use this energy to transport a variety of molecules across cell membranes including metabolic products, lipids, sterols, and drugs. ABC proteins play a wide variety of physiological roles, and are of considerable clinical importance. In humans, 14 ABC genes have been associated with genetic diseases including Tangier disease, immune deficiency disorders, Dubin-Johnson Syndrome, progressive familial intrahepatic cholestasis type II, and cystic fibrosis. Several members of the ABCB and ABCC subfamilies have been shown to play a significant role in mediating multidrug resistance by functioning as ATP-dependent export pumps for chemotherapeutic agents. Select proteins of these subfamilies appear to account for all multidrug resistance observed in human and rodent cells. Unlike most ABC transporters that are relatively substrate specific, transporters of the ABCB and ABCC subfamilies exhibit remarkably broad substrate specificity. Over expression of select genes in tumor cells is believed to mediate the efficient export of drugs, thereby reducing the pharmacologic doses.
Regulation of expression of these clinically important genes is not well understood. This project implements comparative computational approaches to identify conserved regulatory regions in genes of the ABCB and ABCC subfamilies. Results from this project will provide insight into the molecular mechanisms that drive ABCB and ABCC gene expression and the role of these genes play in regulatory networks that respond to external stimuli, including clinical drug treatments.
Another major focus of research is development of the publicly available Comparative Toxicogenomics Database (CTD; http://ctd.mdibl.org). Chemicals in the environment play a critical role in the etiology of many human diseases. Despite their prevalence, the molecular mechanisms of action and the effects of chemicals on susceptibility to disease are not well understood. To promote understanding of these mechanisms, CTD presents scientifically reviewed and curated information on chemicals, relevant genes and proteins, and their interactions in vertebrates and invertebrates. CTD integrates sequence, reference, species, microarray, and general toxicology information to provide a unique centralized resource for toxicogenomic research. The database also provides visualization capabilities that enable cross-species comparisons of gene and protein sequences. These comparisons will facilitate understanding of structure-function correlations and the genetic basis of susceptibility. Manual curation and integration of cross-species chemical-gene and chemical-protein interactions from the literature are now underway. These data will provide information for building complex interaction networks.
Publications
C. B. Congdon, J. Aman, G. M. Nava, H. R. Gaskins, C. Mattingly, "An evaluation of information content as a metric for the inference of putative conserved non-coding regions in DNA sequence using a genetic algorithms approach", IEEE/ACM TCBB, 13 June 2007. <http://doi.ieeecomputersociety.org/10.1109/TCBB.2007.1059>
Clare Bates Congdon, H. Rex Gaskins, Joseph Aman, Gerardo M. Nava, and Carolyn Mattingly. High Information Content Is Not What We Seek: Extended Experiments with GAMI. Bull MDIBL. 2007; 46.
Carolyn Mattingly, Jeffrey D. Calhoun and Antonio Planchart. Preliminary investigations indicate that Crot and Abcb genes from the spiny dogfish (Squalus acanthias) are syntenic. Bull MDIBL. 2007; 46.
C. B. Congdon, H. R. Gaskins, G. M. Nava, C. Mattingly, Towards Interactive Visualization for Exploring Conserved Motifs in Noncoding DNA Sequence. In Proceedings of Frontiers in the Convergence of Bioscience and Information Technologies 2007 (FBIT 2007), IEEE Press, 2007.Mattingly CJ, Colby GT, Rosenstein MC, Forrest JN, Boyer JL. Cross-Species Comparative Approaches to Understanding Chemical-Gene Interactions. J. Exp Zool 2006 Sep 1;305(9):689-92.
Mattingly CJ, Rosenstein MC, Davis AP, Colby GT, Forrest JN, Boyer JL. The Comparative Toxicogenomics Database (CTD): A Cross-Species Resource for Building Chemical-Gene Interaction Networks. ToxSci 2006 Aug;92(2):587-95.
Congdon CB, Fizer CW, Smith NW, Gaskins HR, Aman J, Mattingly C. Preliminary Results for GAMI: A Genetic Algorithms Approach to Motif Inference. Proceedings of the 2005 IEEE Symposium on Computational Intelligence in Bioinformatics and Computational Biology (CIBCB, La Jolla, California) 2005, pp. 97-104.
Barnes DW, Mattingly C, Parton A, Dowell LM, Bayne CJ, Forrest JN. Marine organism cell biology and regulatory sequence discovery in comparative functional genomics. Cytotechnology. 2005 43:123-137.
Mattingly C, Parton A, Dowell L, Rafferty J, Barnes D. Cell and Molecular Biology of Marine Elasmobranchs: Squalus acanthias and Raja erinacea. Zebrafish. 2004 1(2): 111-120.
Abstracts Presented at Scientific Meetings
Davis AP, Mattingly CJ, Rosenstein MC, Wiegers T, Forrest JN, Boyer JL. The Comparative Toxicogenomics Database: connecting chemicals, genes, and diseases. Society of Toxicology. March 25-29, 2007. Charlotte, NC, USA.
AP Planchart and CJ Mattingly. 2nd Northeast Regional IDeA Meeting, Burlington VT, Leveraging genomic conservation in the spiny dogfish (Squalus acanthias)for comparative functional studies of the ABCB gene subfamily (poster), August 2007.
AP Planchart and CJ Mattingly. Center for Membrane Toxicity Studies, External Research Advisory Committee Meeting, MDIBL, Salisbury Cove, ME, July, 2007. Potential Synergistic Effects of Arsenic and Estrogenic Compounds on Vertebrate Embryonic Development in Danio rerio.
A. Planchart and C.J. Mattingly, 47th Annual Society of Toxicology Meeting, Seattle WA. March, 2008. Arsenic perturbation of gene networks during vertebrate development.
C.J. Mattingly. 47th Annual Society of Toxicology Meeting, Seattle WA. March, 2008. Using the Comparative Toxicogenomics Database to identify chemical-gene-disease associations: arsenic as a case study
C.J. Mattingly, NERC International Collaboration Initiative: Bioinformatics Workshop, March 2008, Birmingham, UK. The Comparative Toxicogenomics Database (CTD): Promoting understanding of chemical-gene-disease associations.
Mattingly C, Aman J, Congdon CB. Identification of Conserved Non-coding Regions in the ATP Binding Cassette Family of Genes. First Biennial National IDeA Symposium of Biomedical Research Excellence (NISBRE), July 2006.
Mattingly CJ, Rosenstein MC, Davis AP, Colby GC, Forrest JN, Boyer JL. Comparative Toxicogenomics Database (CTD): Promoting Understanding of Chemical-Gene Interactions Keystone: The Molecular and Integrative Basis for Toxic Responses. Victoria, BC. May 2006.
Mattingly CJ, Colby GT, Rosenstein MC, Forrest JN, Boyer JL*. The Comparative Toxicogenomics Database (CTD). Society of Toxicology Annual Meeting. San Diego, CA. March 2006.
Congdon CB, Fizer CW, Smith NW, Gaskins HR, Aman J, Mattingly C. Preliminary Results for GAMI: A Genetic Algorithms Approach to Motif Inference. IEEE Symposium on Computational Intelligence in Bioinformatics and Computational Biology. La Jolla, CA. November 2005.
Mattingly CJ, Colby GT, Rosenstein MC, Forrest JN, Boyer JL. Cross-Species Comparative Approaches to Understanding Chemical-Gene Interactions. 15th International Conference of Comparative Endocrinology. Boston, MA. May 2005
Mattingly CJ. Comparative Approaches to Understanding Gene Chemical Interactions. Northland Chapter of the Society of Toxicology Meeting. Minneapolis, MN. April 2005.
Mattingly CJ. Cross-species comparative studies of ABC genes 32ndMaine Biological and Medical Sciences Symposium. Salisbury Cove, ME. April 2005.
Mattingly CJ, Colby GT, Rosenstein MC, Forrest JN, Boyer JL. Comparative Toxicogenomics Database. Society of Toxicology Annual Meeting. New Orleans, LA. March 2005.
Mattingly CJ, Colby GT, Rosenstein MC, Forrest JN, Boyer JL. The Comparative Toxicogenomics Database (CTD): Comparative Molecular Approaches to Environmental Health Research. American Chemical Society National Meeting. Philadelphia, CA. August 2004.