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

DNA methylation of imprint control regions associated with Alzheimer's disease

7 May 2024: Using WGBS and the recently identified human imprintome (Jima et al., 2022), we provide the first evidence that DNA methylation in 120 candidate imprint control regions (ICRs) varies markedly in the brains of people with Alzheimer's disease (AD) versus that in controls (Cevik et al., 2024).

Eighty-one and 27 ICRs were differentially methylated in non Hispanic blacks (NHBs) and non Hispanic whites (NHWs), respectively. Interestingly, only two ICRs were in common to both populations, those that are proximal to a known imprinted gene, MEST/MESTIT1 (ICR_481) and the inflammasome gene, NLRP1 (ICR_987). The three fold increased in the frequency of ICRs with methylation changes in NHBs with AD compared to that in NHWs with AD may contribute to the higher prevalence of AD in NHBs (Alzheimer's Association, 2023).

These findings are also consistent with the developmental origins of health and disease (DOHaD) hypothesis. It postulates that an increased susceptibility to adult-onset chronic diseases, such as AD, frequently have their origins in early development (Gauvrit et al., 2022), and support the findings that AD is characterized by changes in the brain that likely start decades before the clinical symptoms appear (Beason-Held et al., 2013). Thus, alteration in ICR methylation may serve as an early detection tool of AD risk that is essential for slowing the progression of this disease.

In conclusion, these findings indicate that early developmental alterations in the DNA methylation of regions regulating genomic imprinting contribute to AD risk, and that this epigenetic risk differs significantly between NHBs and NHWs.

Twentieth Anniversary of the Agouti Mouse Study

In 1953 Watson and Crick determined the structure of DNA. Fifty years later Waterland and Jirtle demonstrated with the Agouti Mouse Study that the fetal origins of adult disease susceptibility results from alterations in the epigenome - the genetic programs that tell the genes when, where and how to work. Thus, not only mutations in the genome, but also changes in the epigenome function in the genesis of human health and disease. Read more...

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...