Rick Woychik, Ph.D.
Molecular Carcinogenesis Laboratory / Mammalian Genome Group
The Mammalian Genome Group is broadly interested in understanding the role of epigenomic transcriptional regulation in an organism's response to environmental exposures. We are specifically interested in studying the role of repetitive elements in these processes.
All mammalian genomes are comprised of a large assortment of different classes repetitive elements (RE's) that include LINE's, intracisternal A particles (IAP's), VL30 elements, endogenous retroviral elements (ERV's), SINE's, transposons, and various other types of repetitive elements. These RE's are distributed across the entire genome and are highly abundant; in fact, it has been estimated that RE's comprise over 50% of a typical mammalian genome. Many of these elements have powerful regulatory elements and exhibit complex patterns of transcriptional expression throughout mammalian development.
Most notably, these RE's have the potential to actively interfere with the normal transcription of genes located in their immediate vicinity along the chromosome. We originally described one of the first instances of how a RE can interfere with the normal expression of a gene. In this case, a promoter within the LTR of an IAP element, located within an intron, was demonstrated to "hijack" the normal regulated expression of the agouti gene in the skin. This ultimately was shown to result in the ubiquitous expression of the agouti protein, a yellow coat color, obesity and type II diabetes. Interestingly, we showed that the ability of the IAP element to "hijack" the expression of the agouti gene is dependent upon the epigenetic status of the IAP: repressive epigenetic marks effectively silence the ability of the IAP to "hijack" the expression of the gene. Later other groups demonstrated that the differential epigenetic modification of the IAP in the Avy mouse is influenced by environmental exposures. More recently other IAP's and VL30 elements were also shown to influence the expression of adjacent genes.
Given our early work on the Avy allele and the fact that there are nearly 5 million RE's integrated across the mammalian genome, we are in the process of examining how many other genes have patterns of expression that can be influenced by adjacent RE's. Our specific interest is to better understand how changes in the epigenetic marks over RE's can influence non-RE gene expression, and how these changes in gene expression can ultimately influence phenotypes associated with environmental exposures.
Finally, while there is only limited data on the regulation and biological function of RE's, it is clear that their expression respond to changes in diet, oxygen levels, DNA damaging agents and other environmental toxicants, pointing to their modulation by environmental cues. As these factors also modulate mitochondrial metabolism, these findings raise the intriguing possibility that mitochondrial function can regulate the nuclear epigenome, including the expression of REs. Therefore, we are undertaking a series of experiments to understand the role of mitochondria on the regulation and biological impact of RE expression.
Our group utilizes state-of-the-art NextGen genome analysis technologies, bioinformatics, as well as molecular and genetic methods. We actively work to foster interdisciplinary exchanges with postdoctoral fellows integrating Bioinformatics, Statistics, Genetics, Biochemical and Molecular Biology approaches.
Dr. Richard Woychik is Director of the National Institute of Environmental Health Sciences and the National Toxicology Program as well as PI for the Mammalian Genome Research Group in the Division for Intramural Research at NIEHS. He is a molecular geneticist with a Ph.D. in molecular biology from Case Western Reserve University and postdoctoral training with Dr. Philip Leder at Harvard Medical School. He spent almost 10 years at Oak Ridge National Laboratory rising in the ranks to become head of the Mammalian Genetics Section and then director of the Office of Functional Genomics. In August 1997, he assumed the role of vice chairman for research and professor in the Department of Pediatrics at Case Western Reserve University. In 1998, he moved to the San Francisco Bay area, first as the head of the Parke-Davis Laboratory for Molecular Genetics and then as chief scientific officer at Lynx Therapeutics. He returned to academics as the president and CEO of The Jackson Laboratory in August 2002 and served in that role until January 2011. He began his current position in February 2011.
- Lozoya OA, Wang T, Grenet D, Wolfgang TC, Sobhany M, Ganini da Silva D, Riadi G, Chandel N, Woychik RP, Santos JH. Mitochondrial acetyl-CoA reversibly regulates locus-specific histone acetylation and gene expression. Life Sci Alliance. 2019;2(1).
- Lozoya OA, Santos JH, Woychik RP. A Leveraged Signal-to-Noise Ratio (LSTNR) Method to Extract Differentially Expressed Genes and Multivariate Patterns of Expression From Noisy and Low-Replication RNAseq Data. Front Genet. 2018;9:176.
- Lozoya OA, Martinez-Reyes I, Wang T, Grenet D, Bushel P, Li J, Chandel N, Woychik RP, Santos JH. Mitochondrial nicotinamide adenine dinucleotide reduced (NADH) oxidation links the tricarboxylic acid (TCA) cycle with methionine metabolism and nuclear DNA methylation. PLoS Biol. 2018;16(4):e2005707.
- Martínez-Reyes I, Diebold LP, Kong H, Schieber M, Huang H, Hensley CT, Mehta MM, Wang T, Santos JH, Woychik R, Dufour E, Spelbrink JN, Weinberg SE, Zhao Y, DeBerardinis RJ, Chandel NS. TCA Cycle and Mitochondrial Membrane Potential Are Necessary for Diverse Biological Functions. Mol Cell. 2016;61(2):199-209.
- Wang T, Santos JH, Feng J, Fargo DC, Shen L, Riadi G, Keeley E, Rosh ZS, Nestler EJ, Woychik RP. A Novel Analytical Strategy to Identify Fusion Transcripts between Repetitive Elements and Protein Coding-Exons Using RNA-Seq. PLoS One. 2016;11(7):e0159028.
Related Scientific Focus Areas
Genetics and Genomics
Molecular Biology and Biochemistry
This page was last updated on Friday, October 4, 2019