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Studies

Mammalian Genome Group

The Mammalian Genome Group conducts the following studies within the Laboratory of Molecular Carcinogenesis.

Hijacking agouti gene expression

Repetitive elements (REs) have the potential to actively interfere with the normal transcription of genes located in their immediate vicinity along the chromosome. The Mammalian Genome Group 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 on the long terminal repeat (LTR) of an an intracisternal A particle (IAP) element, located within an intron, was demonstrated to "hijack" the normal regulated expression of the agouti gene in the skin. The finding was ultimately shown to result in the ubiquitous expression of the agouti protein which, in turn, was associated with a yellow coat color, obesity, and type II diabetes in mice (1, 2). 

Most notably, the group also previously showed that the ability of the IAP to hijack the expression of agouti is dependent upon the epigenetic status of the IAP:  methylation of the IAP to suppress its ability to influence agouti expression (2). Moreover, other groups have demonstrated that the differential epigenetic modification of the IAP in the agouti mutant is influenced by environmental, nutritional and chemical exposures (3-6). 

Understanding how epigenetics influence non-RE expression

Given the early work on agouti and the fact that there are nearly 5 million RE loci across the mammalian genome, the group is examining whether there are other genes whose expression is influenced by REs. The group aims to better understand how changes in the epigenetic marks over REs can influence the expression of genes within specific cells types, and how these changes in gene expression can ultimately influence phenotypes associated with environmental exposures.       

The role of mitochondria on the regulation and biological impact of RE expression

While there is only limited data on the regulation and biological function of REs, it is clear that their expression responds to changes in diet, oxygen levels, DNA damaging agents, and other environmental toxicants, pointing to their modulation by environmental cues. The fact that these factors also modulate mitochondrial metabolism raises the intriguing possibility that mitochondrial function could regulate the nuclear epigenome, including the expression of REs. Therefore, the Mammalian Genome Group will undertake a series of experiments to better understand the role of mitochondria on the epigenomic regulation of gene expression within the nucleus.

References:

  1. Bultman, S.J., E.J. Michaud, and R.P. Woychik. Characterization of the mouse agouti locus. 1992 Cell 71:1195-1204.
  2. Michaud, E.J., M.J. van Vugt, S.J. Bultman, H.O. Sweet, M.T. Davisson, and R.P. Woychik.  Differential expression of a new dominant agouti allele (Aiapy) is correlated with methylation state and is influenced by parental lineage. 1994 Genes & Dev. 8:1463-1472.
  3. Duhl, DMJ, Vrieling, H, Miller, KA, Wolff, GL, Barsh, GS. 1994 Nature Genet. 8:59-65.
  4. Waterland RA, Jirtle RL.Transposable elements: targets for early nutritional effects on epigenetic gene regulation. Mol Cell Biol. 2003 Aug;23(15):5293-300.
  5. Dolinoy DC, Weidman JR, Waterland RA, Jirtle RL. Maternal genistein alters coat color and protects Avy mouse offspring from obesity by modifying the fetal epigenome. Environ Health Perspect. 2006 Apr;114(4):567-72.
  6. Bernal AJ, Dolinoy DC, Huang D, Skaar DA, Weinhouse C, Jirtle RL. Adaptive radiation-induced epigenetic alterations mitigated by antioxidants. FASEB J. 2013 Feb;27(2):665-71.

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