Charles R. Vinson, Ph.D.
I use genomic assays to study regulated gene expression, focusing on the C/EBP family of transcription factors (TFs) that bind sequence-specific DNA containing methylated cytosines (5mC) in CG dinucleotides. The C/EBP family of TFs binds in the methylated regions of the genome and I am focusing on understanding how the methylated regions communicate with the unmethylated regions to activate gene expression. In parallel, I am using Agilent microarrays containing thousands of DNA features to explore sequence-specific DNA binding of TFs. I can methylate the arrays and examine the consequences on DNA binding.
1) transcription factors, 2) coiled-coil, 3) CG methylation, 4) DNA binding
Gene Regulation and Function: The bZIP Proteins
The regulation of gene expression underlies all cellular processes, including cancer. I am developing new gene-based protein methods to regulate genes, including (1) dominant-negatives (DNs) that inhibit the DNA binding of endogenous transcription factors, resulting in modulation of gene expression, and (2) gain-of-function genes that bind new DNA sequences, resulting in new gene expression. I have developed dominant-negatives to the dimeric B-ZIP (CREB, PAR, AP-1, and C/EBP) and B-HLH-ZIP (USF, Myc, and Mi) transcription factors. These dominant-negatives contain the dimerization domain of the transcription factor and an acidic protein sequence that replaces the basic region. The dominant-negatives heterodimerize with the endogenous transcription factors and prevent DNA binding. I am studying in detail the structural rules that regulate leucine zipper dimerization specificity and sequence-specific DNA binding.
My recent work suggests that intracellular regulation of magnesium has profound effects on the sequence-specific DNA binding of B-ZIP proteins and highlights the possibility that magnesium may be an intracellular second messenger, similar to its larger cousin, calcium. I have expressed a dominant-negative that inhibits both the C/EBP and JUN family of transcription factors in fat tissue. The resulting mouse is "fatless" and has severe diabetes. Using the new microarray technology, I am characterizing the genes that are misregulated. I am starting a project to examine the blood serum from these mice to identify missing peptides as possible hormones secreted from fat. This could have profound implications for the regulation of energy homeostasis. I am expressing these DNs in an inducible manner in transgenic mice to generate new phenotypes and identify transcriptional targets. Preliminary results obtained in collaboration with others indicate that expression of a dominant-negative to Jun (A-Fos) inhibits tumor formation. I have also placed these DNs into adenoviral vectors. I have shown that expression of A-Fos potentiates killing of the chemotherapeutic resistant cell lines. I am extending these studies to determine if expression of A-Fos selectively kills cancer cells.
Selected Recent Publications
- Biochim Biophys Acta Gene Regul Mech. 1862(4): 486-492, 2019. [ Journal Article ]
Replacing C189 in the bZIP domain of Zta with S, T, V, or A changes DNA binding specificity to four types of double-stranded DNA.Biochem Biophys Res Commun. 501(4): 905-912, 2018. [ Journal Article ]
Delayed Hair Follicle Morphogenesis and Hair Follicle Dystrophy in a Lipoatrophy Mouse Model of Pparg Total Deletion.J Invest Dermatol. 138(3): 500-510, 2018. [ Journal Article ]
- Science. 356(6337): pii: eaaj2239. doi: 10.1126/science.aaj2239, 2017. [ Journal Article ]
Distal CpG islands can serve as alternative promoters to transcribe genes with silenced proximal promoters.Genome Res. 27(4): 553-566, 2017. [ Journal Article ]
Dr. Charles Vinson received his Ph.D. from the University of Virginia studying Drosophila developmental genetics with Dr. Paul Adler. He subsequently carried out postdoctoral work at the Carnegie Institution of Washington in Baltimore, MD, with Dr. Steven McKnight, and joined the NCI as a tenure track investigator in 1991.
|Sreejana Ray Ph.D.||Postdoctoral Fellow (Visiting)|