Carreras-Gallo, et. al. bioRxiv (Jan 2024)
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22 July 2024: The monoallelic parent-of-origin dependent expression of imprinted genes is regulated by differentially methylated imprint control regions (ICRs) - the human imprintome. The epigenetic dysregulation of the imprintome by environmental exposures during early development results in the fetal origins of behavioral disorders and common chronic diseases. Whole genome bisulfite sequencing (WGBS) is a unique method to profile these ICRs (Cevik, et. al. 2024); however, it is computationally intensive since it requires high coverage, making it expense for use in large epidemiological studies.
To address this deficiency, we developed a custom methylation array containing 22,819 probes (Carreras-Gallo et al. 2024). Among them, 10,438 are CG probes targeting unique CpG sites, with 9,757 probes successfully mapping to 1,088 out of the 1,488 candidate ICRs recently described (Jima et al. 2022). Our custom array will be useful for replicable and accurate DNA methylation assessment, mechanistic insight, and targeted investigation of ICRs in the human imprintome. This tool should accelerate the discovery of ICRs associated with a wide range of diseases and exposures, and advance our understanding of genomic imprinting and its relevance in development and disease formation throughout the life course.
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). Read more...
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...
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 mothers and fathers imprinted genes during development has been postulated to explain 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). Read more...
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...
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...