As these GEITP pages have often described, an individual’s genotype — determined by DNA sequence differences — contributes to any heritable trait (phenotype) such as type-2 diabetes, schizophrenia, risk of coronary artery disease, or response to a drug or environmental toxicant. On the other hand, epigenetic effects — determined by chromosomal events other than DNA sequence differences — also contribute to many complex traits, but they are not usually inherited but rather acquired during one’s life, due to environmental or other pressures. Epigenetic effects include DNA-methylation, RNA-interference (RNAi; microRNA regulation), histone modifications, and chromatin remodeling. Assays are readily available for the first two, but the latter two are still under intense investigation.
MicroRNAs (miRs) constitute an abundant class of noncoding RNA molecules (i.e. they don’t make protein) that are endogenously expressed in multicellular organisms. These miRs are 18–23 nucleotides in length, and they often regulate gene expression by messenger-RNA (mRNA) degradation or translational repression (blocking the process of going from mRNA to the protein). Many miRs show high levels in brain, and are known to contribute to brain development, neural plasticity, and neuroprotection. The levels of many miRs are altered in neurodegenerative diseases (e.g. 35 miRs were shown to be altered in prefrontal cortex of late-onset Alzheimer Disease patients). If one deletes Dicer (a critical enzyme involved in miR synthesis) in adult brain — this results in Tau hyperphosphorylation and neuronal loss, which are the pathological traits associated with tau-opathy (i.e. manifested as deposition of intracellular neurofibrillary tangles). However, it is not known whether or not miR changes are already present at the presymptomatic stages of neurodegenerative diseases, and if such miR changes can directly impact biological pathways that may subsequently lead to neurodegeneration.
Tau-opathies include a wide range of neurodegenerative diseases such as progressive supranuclear palsy, Pick’s disease, parkinsonian tremor linked to chromosome 17, and Alzheimer Disease. Previously, miRs have been identified as modulators of Tau that contribute to Tau pathology. Authors [see attached article] first determined which (mouse brain hippocampal) miRs might be altered at the presymptomatic and symptomatic stages of
tau disease using the “Tau mouse” (rTg4510 mouse), which is a well-characterized lab animal model. By pairing analysis of miR-RNA, using QIAGEN Ingenuity Pathway Analysis (IPA), authors found 401 genes that can be regulated by 71 miRs altered in the Tau mouse hippocampus at the presymptomatic stage. Among several miRs confirmed experimentally, miR142−3p and miR142−5p in the Tau hippocampus was significantly up-regulated by 2 weeks of age and later in life.
Transcriptome studies by RNA-seq and IPA revealed several overlapping biological and disease-associated pathways affected by either Tau or miR142 over-expression — including ‘signal transducer & activator of transcription-3’ (Stat3) and ‘tumor necrosis factor receptor-2’ (Tnfr2) signaling pathways. Similar to what was observed in Tau brains, over-expression of miR142 in cortical neurons of wild-type mice augments mRNA levels of ‘glial fibrillary acidic protein’ (Gfap) and ‘colony-stimulating factor-1’ (Csf1), accompanied by a significant increased numbers of microglia and reactive astrocytes. Taken together, these data suggest that miR alterations by Tau over-expression appear to contribute to the phenotype of neuroinflammation that is seen in the brains of Tau mice. This is an excellent example of an epigenetic effect influencing the individual’s phenotype.
Sci Rep (Nature) 2018; 8: 9251