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

Human Imprintome Genomic Map

19 July 2022: Genomic imprinting is a unique epigenetic form of gene regulation that evolved in marsupials and placental mammals about 150 million years ago (Imprinting Evolution in Mammals). It results in only one copy of a gene being expressed in a parent-of-origin dependent manner. Thus, imprinted genes are disease susceptibility loci since a single genetic or epigenetic event can alter their function.

Imprinted genes are heavily involved in metabolism and growth regulation. An epigenetic tug-of-war between the mother's and father's imprinted genes during development has been postulated to explain the evolution of imprinting (Moore and Haig, 1991), and variations in the fetal origins of metabolic disorders such as obesity and type 2 diabetes, as well as cancer, and a spectrum of mental disorders ranging from autism to schizophrenia (Badcock and Crespi, 2008).

Using whole genome bisulfite sequencing, our investigation identified 1,488 hemimethylated DNA candidate imprint control regions (ICRs) in the human genome that potentially regulate parental-specific expression of imprinted genes, The Human Imprintome (Dereje et al, 2022). Furthermore, gamete methylation approached 0% or 100% in 332 ICRs (178 paternally and 154 maternally methylated), supporting parent-of-origin-specific methylation (Imprintome Website).

Many of the novel ICRs identified are in regions previously implicated in the pathogenesis of human diseases. For example, candidate differentially methylated ICRs are located within the Down syndrome (DS) critical region at chromosome 21q22, and within the DiGeorge syndrome critical region at chromosome location 22q11.2. A total of 98 candidate ICRs are also identified on the human X-chromosome. DHRSX resides in pseudoautosomal region 1, but interestingly, most ICRs on the X chromosome are not in pseudoautosomal regions.

The imprintome consists of the hemimethylated genomic regions that control monoallelic expression of imprinted genes; it is NOT the repertoire of these genes. A novel tool for scientists, the human imprintome, will help elucidate the role of imprinted genes in the development of diseases and disorders and in the evolution of mammals. Furthermore, since ICRs are established before tissue differentiation, cell samples used in environmental epigenomic studies can be those readily available to epidemiologists (e.g., white blood cells and buccal epithelial cells).

KCNK9 Loss of Imprinting in Triple Negative Breast Cancer

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. Read more...

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...