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

KCNK9 Loss of Imprinting in Triple Negative Breast Cancer

7 January 2022: We previously predicted and experimentally demonstrated that KCNK9 is imprinted in humans, and maternally expressed in the brain (Luedi et al, 2007). We now show that KCNK9 is also expressed only from the maternal allele in breast epithelium, and that loss of imprinting at this locus is linked to the pathogenesis of triple negative breast cancer (TNBC) (Skaar et al, 2021).

Genomic imprinting is an inherited form of parent-of-origin specific epigenetic gene regulation that is dysregulated by poor prenatal nutrition and environmental toxins. KCNK9 encodes for TASK3, a pH-regulated potassium channel membrane protein. It is overexpressed in 40% of breast cancer; however, gene amplification accounts for increased expression in less than 10% of these cancers.

We have now identified a differentially methylated region (DMR) associated with KCNK9 imprinting. Hypomethylation of this DMR is coupled with biallelic expression of KCNK9 and TASK3 overexpression in 63% of TNBC. This association is highly significant in African-Americans (p = 0.006), but not in Caucasians (p = 0.70). KCNK9 hypomethylation is also present in the non-cancerous breast epithelium in 77% of women at high-risk of developing breast cancer. Furthermore, hypomethylation of the KCNK9 DMR enhances mitochondrial membrane potential and apoptosis resistance. Thus, KCNK9 loss of imprinting in TNBC may provide a novel epigenetic target for the diagnosis, prevention, and treatment of TNBC, particularly in African-Americans.

Fifty Years of Research - Randy L. Jirtle

In the past 50 years, I have gone from the physical to the biological sciences, and from studying tumor vascularity and blood flow to determine the human imprintome. It has been an exciting journey! Read more...

I had an Epiphany: Desire to Voluntarily Exercise May Be Epigenetically Determined in the Womb

Should I go to the gym and exercise or sit on the couch and watch a movie? This is a question that we have all asked ourselves many times!

Robert Waterland and his research group at Baylor College of Medicine have provided the first evidence that voluntary expenditure of energy, at least in mice, is determined in part by epigenetic changes established in early development (MacKay et al., Nat Commun, 2019).

This study showed that hypothalamic AgRP neuron-specific knockout of Dnmt3a leads to cell type-specific disruption of DNA methylation and the developmental upregulation of 1681 genes and downregulation of 2063 genes in these neurons, resulting in a decrease in voluntary exercise. Specifically, AgRP neuron-specific hypomethylation of the Bmp7 Read more...

William G. Kaelin, Jr. - Recipient of the 2019 Nobel Prize in Physiology or Medicine

William G. Kaelin Jr., Peter J. Ratcliffe and Gregg L. Semenza are this year's recipients of the Nobel Prize in Physiology or Medicine "... for their discoveries of how cells sense and adapt to oxygen availability."

When I joined the faculty at Duke University, I was investigating tumor oxygenation and blood flow regulation. At that time, third year Duke medical students were required to perform a research project. Bill Kaelin asked to do research in my lab in the early 1980s because of his early interest in tumor oxygenation. He demonstrated that the calcium antagonists verapamil and flunarizine significantly increased tumor blood flow, indicating their potential usefulness in improving cancer treatment with both chemotherapeutic agents and ionizing radiation.

Ultimately, his interest in the regulation of tissue oxygenation le Read more...

Jirtle Receives EMGS 2019 Alexander Hollaender Award

The Environmental Mutagenesis and Genomics Society (EMGS) Environmental Mutagenesis and Genomics Society (EMGS) honors its first president and Founder, Alexander Hollaender, by conferring the Hollaender Award annually in recognition of outstanding contributions in the application of the principles and techniques of environmental mutagenesis to the protection of human health.

This year, EMGS recognizes Dr. Jirtle's discovery that the environment can influence inheritance of phenotypic traits through epigenetic reprogramming representing one of the most important scientific advances of the 21st century. To quote his nominators: "His pioneering work in epigenetics and genomic imprinting has uncovered a vast territory in which a gene represents less of an inexorable sentence and more of an access point for the environment to modify the genome.&qu Read more...

Pioneer Scientists: Jack Fowler and Alfred Knudson

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. Read more...