Cell fate is determined by sets of genes that are expressed in a programmed manner during development and cellular differentiation. Often, in diseases as diverse as diabetes and cancer, malfunctioning transcriptional regulators produce aberrant patterns of gene expression that are at the heart of the ailment. How regulatory proteins find their binding sites and regulate their targeted genes remains a central question in the field. ? ? We combine chemical and biological approaches to study otherwise intractable features of transcriptional regulators. We utilize sequence-specific DNA binding compounds (polyamides) to target specific DNA sequences, and they can be readily modified to bear a rich array of functional modules. In the proposed work, we will elucidate the basis of cooperative DNA binding by Extradenticle and Ultrabithorax, two highly conserved developmental regulators. We will apply that understanding to develop precisely tailored synthetic regulators that target genes cooperatively with cell-type specific transcription factors. Finally, we will test the ability of our artificial transcription factors to regulate genes in cells and in living organisms. ? ? The ultimate goal of our work is to generate small molecules that can regulate the expression of targeted genes in a desired manner. As designer transcription factors, these molecules will have tremendous value in dissecting transcriptional networks that govern cell fate and disease. They also have potential as therapeutic agents for a variety of diseases that are caused by aberrant transcriptional regulation. ? ?
| Warren, Christopher L; Zhao, Jianfei; Glass, Kimberly et al. (2012) Fabrication of duplex DNA microarrays incorporating methyl-5-cytosine. Lab Chip 12:376-80 |
| Campbell, Zachary T; Bhimsaria, Devesh; Valley, Cary T et al. (2012) Cooperativity in RNA-protein interactions: global analysis of RNA binding specificity. Cell Rep 1:570-81 |
| Ansari, Aseem Z; Peterson-Kaufman, Kimberly J (2011) A partner evokes latent differences between Hox proteins. Cell 147:1220-1 |
| Carlson, Clayton D; Warren, Christopher L; Hauschild, Karl E et al. (2010) Specificity landscapes of DNA binding molecules elucidate biological function. Proc Natl Acad Sci U S A 107:4544-9 |
| Rodríguez-Martínez, José A; Peterson-Kaufman, Kimberly J; Ansari, Aseem Z (2010) Small-molecule regulators that mimic transcription factors. Biochim Biophys Acta 1799:768-74 |
| Peterson-Kaufman, Kimberly J; Carlson, Clayton D; Rodríguez-Martínez, José A et al. (2010) Nucleating the assembly of macromolecular complexes. Chembiochem 11:1955-62 |
| Henriques, Sonia Troeira; Tan, Chia Chia; Craik, David J et al. (2010) Structural and functional analysis of human liver-expressed antimicrobial peptide 2. Chembiochem 11:2148-57 |
| Akhtar, Md Sohail; Heidemann, Martin; Tietjen, Joshua R et al. (2009) TFIIH kinase places bivalent marks on the carboxy-terminal domain of RNA polymerase II. Mol Cell 34:387-93 |
| Hauschild, Karl E; Stover, James S; Boger, Dale L et al. (2009) CSI-FID: high throughput label-free detection of DNA binding molecules. Bioorg Med Chem Lett 19:3779-82 |
| Ozers, Mary S; Warren, Christopher L; Ansari, Aseem Z (2009) Determining DNA sequence specificity of natural and artificial transcription factors by cognate site identifier analysis. Methods Mol Biol 544:637-53 |
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