TY - JOUR
T1 - The EDGE hypothesis
T2 - Epigenetically directed genetic errors in repeat-containing proteins (RCPs) involved in evolution, neuroendocrine signaling, and cancer
AU - Ruden, Douglas M.
AU - Jamison, D. Curtis
AU - Zeeberg, Barry R.
AU - Garfinkel, Mark D.
AU - Weinstein, John N.
AU - Rasouli, Parsa
AU - Lu, Xiangyi
N1 - Funding Information:
This research was supported in part by the Environmental Health Sciences Center in Molecular and Cellualr Toxicology with Human Applications Grant P30 ES06639 at Wayne State University to D.M.R., P.R., and X.L., the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research for B.N.Z. and J.N.W., NIH R01 grant (DK 07173) to X.L. NIH R01 grants (ES012933 and CA105349) to D.M.R., and a Center for Nutrient Gene Interaction in Cancer Prevention (CNGI) grant to M.D.G. Finally, we thank David Crews and Anna Jang for critically reading the manuscript.
PY - 2008/6
Y1 - 2008/6
N2 - Trans-generational epigenetic phenomena, such as contamination with endocrine-disrupting chemicals (EDCs) that decrease fertility and the global methylation status of DNA in the offspring, are of great concern because they may affect health, particularly the health of children. However, of even greater concern is the possibility that trans-generational changes in the methylation status of the DNA might lead to permanent changes in the DNA sequence itself. By contaminating the environment with EDCs, mankind might be permanently affecting the health of future generations. In this section, we present evidence from our laboratory and others that trans-generational epigenetic changes in DNA might lead to mutations directed to genes encoding amino acid repeat-containing proteins (RCPs) that are important for adaptive evolution or cancer progression. Such epigenetic changes can be induced "naturally" by hormones or "unnaturally" by EDCs or environmental stress. To illustrate the phenomenon, we present new bioinformatic evidence that the only RCP ontological categories conserved from Drosophila to humans are "regulation of splicing," "regulation of transcription," and "regulation of synaptogenesis," which are classes of genes likely to be important for evolutionary processes. Based on that and other evidence, we propose a model for evolution that we call the EDGE (Epigenetically Directed Genetic Errors) hypothesis for the mechanism by which mutations are targeted at epigenetically modified "contingency genes" encoding RCPs. In the model, "epigenetic assimilation" of metastable epialleles of RCPs over many generations can lead to mutations directed to those genes, thereby permanently stabilizing the adaptive phenotype.
AB - Trans-generational epigenetic phenomena, such as contamination with endocrine-disrupting chemicals (EDCs) that decrease fertility and the global methylation status of DNA in the offspring, are of great concern because they may affect health, particularly the health of children. However, of even greater concern is the possibility that trans-generational changes in the methylation status of the DNA might lead to permanent changes in the DNA sequence itself. By contaminating the environment with EDCs, mankind might be permanently affecting the health of future generations. In this section, we present evidence from our laboratory and others that trans-generational epigenetic changes in DNA might lead to mutations directed to genes encoding amino acid repeat-containing proteins (RCPs) that are important for adaptive evolution or cancer progression. Such epigenetic changes can be induced "naturally" by hormones or "unnaturally" by EDCs or environmental stress. To illustrate the phenomenon, we present new bioinformatic evidence that the only RCP ontological categories conserved from Drosophila to humans are "regulation of splicing," "regulation of transcription," and "regulation of synaptogenesis," which are classes of genes likely to be important for evolutionary processes. Based on that and other evidence, we propose a model for evolution that we call the EDGE (Epigenetically Directed Genetic Errors) hypothesis for the mechanism by which mutations are targeted at epigenetically modified "contingency genes" encoding RCPs. In the model, "epigenetic assimilation" of metastable epialleles of RCPs over many generations can lead to mutations directed to those genes, thereby permanently stabilizing the adaptive phenotype.
KW - Cancer
KW - Endocrine disruptors
KW - Epigenetics
KW - Evolution
KW - Hsp90
KW - Neuroendocrine signaling
KW - Repeat-containing proteins (RCPs)
KW - Trans-generational epigenetics
KW - Trinucleotide repeats
UR - http://www.scopus.com/inward/record.url?scp=43049180970&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=43049180970&partnerID=8YFLogxK
U2 - 10.1016/j.yfrne.2007.12.004
DO - 10.1016/j.yfrne.2007.12.004
M3 - Review article
C2 - 18295320
AN - SCOPUS:43049180970
SN - 0091-3022
VL - 29
SP - 428
EP - 444
JO - Frontiers in Neuroendocrinology
JF - Frontiers in Neuroendocrinology
IS - 3
ER -