Epigenetic control of enhancers alters neuronal functions and may be involved in Alzheimer’s disease (AD). Here, we identify enhancers in neurons contributing to AD by comprehensive fine-mapping of DNA methylation at enhancers, genome-wide. We examine 1.2 million CpG and CpH sites in enhancers in prefrontal cortex neurons of individuals with no/mild, moderate, and severe AD pathology ( n = 101). We identify 1224 differentially methylated enhancer regions; most of which are hypomethylated at CpH sites in AD neurons. CpH methylation losses occur in normal aging neurons, but are accelerated in AD. Integration of epigenetic and transcriptomic data demonstrates a pro-apoptotic reactivation of the cell cycle in post-mitotic AD neurons. Furthermore, AD neurons have a large cluster of significantly hypomethylated enhancers in the DSCAML1 gene that targets BACE1 . Hypomethylation of these enhancers in AD is associated with an upregulation of BACE1 transcripts and an increase in amyloid plaques, neurofibrillary tangles, and cognitive decline.

Summary In eukaryotes, cytokinesis generally involves an acto-myosin ring, the contraction of which promotes daughter cells segregation. Assembly of the contractile ring is tightly controlled in space and time (see[1–4] for reviews). In the fission yeast, contractile ring components are first organized by the Anillin-like protein Mid1 [5, 6] and Cdr2 kinase [7–9] into medial cortical nodes. These nodes then coalesce laterally into a functional compact contractile ring [10–13]. Although Mid1 is present at the medial cortex throughout G2 phase [14], recruitment of contractile ring components to nodes starts only at mitotic onset [12] indicating that this event is cell cycle regulated. Polo kinases are key temporal coordinators of mitosis and cytokinesis [1] and the Polo-like kinase Plo1 [15] has long been implicated in Mid1 regulation [16]: Plo1 activates Mid1 nuclear export at mitotic onset [16], coupling division plane specification to nuclear position [7]. Here, we provide evidence that Plo1 also triggers the recruitment of contractile ring components into medial cortical nodes. Plo1 binds at least two independent sites on Mid1, including a consensus site phosphorylated by Cdc2. Plo1 phosphorylates several residues within the first 100 amino acids of Mid1, which directly interact with the IQGAP Rng2 [17], and influences the timing of Myosin II recruitment. Plo1 thereby facilitates contractile ring assembly at mitotic onset.

Parkinson’s disease (PD) is a prevalent neurodegenerative illness that is often diagnosed after significant pathology and neuronal cell loss has occurred. Biomarkers of PD are greatly needed for early diagnosis, as well as for the prediction of disease progression and treatment outcome. In this regard, the epigenome, which is partially dynamic, holds considerable promise for the development of molecular biomarkers for PD. Epigenetic marks are modified by both DNA sequence and environmental factors associated with PD, and such marks could serve as a unifying predictor of at-risk individuals. Epigenetic abnormalities have been detected in PD and other age-dependent neurodegenerative diseases, some of which were reported to occur early on and were reversible by PD medications. Emerging reports indicate that certain epigenetic differences observed in the PD brain are detectable in more easily accessible tissues. In this review, we examine epigenetic-based strategies for the development of PD biomarkers. Despite the complexities and challenges faced, the epigenome offers a new source of biomarkers with potential etiological relevance to PD, and may expand opportunities for personalized therapies.

Schizosaccharyomyces pombe, like human cells, divide symmetrically through constriction of an acto‐myosin ring. The conserved protein Mid1 plays a key role in the early assembly of the ring. Cells lacking mid1 form acto‐myosin rings that are non‐centered and disorganized, resulting in unequal division of the cellular contents. In human cells a Mid1 related protein called anillin regulates contraction of this ring. Anillin contains an actin binding domain that is necessary for the protein's direct association with actin. Unlike anillin, Mid1 does not contain an actin binding domain, and its ability to interact directly with actin has not been previously reported. However, previous studies show that anillin depleted and Mid1 depleted cells show similar defects in ring placement, ring formation, and cytokinesis. To assess whether or not Mid1 directly associates with actin, in vitro actin binding assays were performed. To further characterize the relationship between Mid1 and the acto‐myosin ring, we tested the ability of actin to bind GST‐Mid1 fragments with and without targeted mutations. Determining which members of the acto‐myosin ring associate directly with actin, an essential ring component, will provide significant insight into the molecular details of cytokinesis.Research supported by NSF‐Advance and GVSU.

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