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'Hot off the press' is a daily listing of the most recent articles in epigenetics and imprinting

Pioneer Scientists: Jack Fowler and Alfred Knudson

21 March 2017: Sir Isaac Newton stated, "If I have seen further, it is by standing on the shoulders of giants.” Two prominent scientists who significantly altered my scientific career died this past year – John Francis (Jack) Fowler and Alfred George Knudson, Jr.

I received my BS in 1970 from the University of Wisconsin (UW) in Nuclear Engineering. I transitioned from the physical to the biological sciences as a graduate student at the UW under the mentorship of Kelly Hardenbrook Clifton. My shift from nuclear engineering to a radiobiology was assisted greatly by Jack Fowler’s pioneering research in tumor oxygenation and the mathematical modeling of the interaction of radiation with normal and malignant tissues during fractionated radiation therapy. Later when I was at Duke University, I invited Dr. Fowler to give an Alpha/Beta Model Workshop and a Lecture on Radiation Fractionation to describe how to maximize the therapeutic effects of radiation in the treatment of cancer.

Alfred Knudson, a physician and cancer geneticist, is widely known for his two-hit hypothesis to explain the incidence of hereditary and nonhereditary forms of retinoblastomas (Knudson PNAS 68: 820-823, 1971). This innovative conceptual framework on how to view the genesis of cancer ultimately led to the identification of the retinoblastoma tumor suppressor gene, RB1 (Friend et al. Nature 223: 643-646, 1986).

Our lab subsequently used the Knudson two-hit hypothesis of tumorigenesis to provide the first evidence that the Insulin like Growth Factor 2 Receptor (IGF2R) also functions as a tumor suppressor (De Souza et al. Nat. Genet.). Since IGF2R is imprinted (i.e. one copy of the gene silenced by DNA methylation), this finding thrusted me into the rapidly growing research field of epigenetics. Interestingly, I had the honor of finally meeting Dr. Knudson almost a decade later in Stockholm, Sweden at the 2004 Nobel Symposium on epigenetics entitled, Epigenetic Reprogramming in Development and Disease. I will greatly miss these pioneering scientists upon whose shoulders I stood.

Imprintome Definition Clarified

Amber Dance published in TheScientist the paper, Characterizing the Imprintome: Three Techniques for Identifying the Collection of Maternal and Paternal Genes Silenced in Offspring.

Although it is important to inform people that scientists are attempting to define this subset of genes in a number of species, “imprintome” is not used in this paper as it was originally intended. The word “imprintome” needs to be used in the precise way we initially defined it so confusion is not introduced into a scientific subject that is already difficult to understand. Read more...

Western Diet Blocks Gut Microbiome Programing of the Host Epigenome

Krautkramer et al. at the University of Wisconsin-Madison demonstrate in this study that the gut microbiome regulates global histone acetylation and methylation not only in the colon, but also in tissues outside the gut (i.e. liver and fat). Moreover, consumption of a ‘‘Western-type’’ diet prevents many of the microbiota-dependent chromatin changes that occur in a polysaccharide-rich diet by limiting the formation of microbial short-chain fatty acids (SCFA). These findings suggest the intriguing possibility that gut microbiome-mediated alterations in the host epigenome may be mechanistically involved in the genesis of chronic diseases, such as cardiovascular disease, obesity, diabetes, inflammatory bowel disorders, and cancer. Waterland and Jirtle prev Read more...

Imprinted Genes Implicated in the Puzzle of Autism

FOXG1 is potentially involved in the development of autism spectrum disorder (ASD). In a recent study, Dr. Vaccarino and her colleagues at Yale University used a novel 3D organoid culture of human neural cells that were derived from induced pluripotent stem cells (iPSCs) obtained from the skin cells of people with and without severe idiopathic ASD. This study provides evidence that FOXG1 overexpression, rather than gene mutation, induces a GABAergic neuron fate that functions as a developmental precursor to ASD. DLGAP2, the other gene listed in the accompanying graphic, has also been implicated in the development of autism in a copy number variation (CNV) analysis of people with ASD. Read more...

Environmental Lead Exposure in Early Childhood Alters Imprinted Gene Regulation

Although lead (Pb) is a neurotoxin, the mechanism by which it effects neurodevelopment, and the acceptable threshold of exposure to the developing child are still unclear. Imprinted genes have one parental allele silenced epigenetically, and they play critical roles in human development (Jirtle and Weidman 2007). In a recent study published in Environmental Health Perspectives, Cathrine Hoyo and her colleagues at North Carolina State University demonstrated, with the use of participants in the Cincinnati Lead Study, that children exposed early in development to high levels of Pb have altered DNA methylation in the regulatory elements of imprinted genes - PEG3, H19/IGF2 and PLAGL1/HYMAI - over three decades after exposure. Read more...

p16 Epimutation Causes Cancer

Hypermethylation of the promoter region of p16 causes cancer and reduces survival in mice according to a recent report by Lanlan Shen and her colleagues in The Journal of Clinical Investigation.

The history of p16 as a human tumor suppressor gene is complex. Only months after gene deletion evidence from a variety of tumor cell lines indicated the involvement of p16 in the genesis of cancer (Nobori et al. 1994; Kamb et al. 1994), its tumor suppressor function was brought into question (Spruck et al. 1994; Cairns et al. 1994).

According to the two-hit theory of carcinogenesis by