Transcriptomic points of departure calculated from human intestinal cells exposed to dietary nanoparticles.

Use of nanoparticles (NPs) in the food industry raises dietary health concerns. Assessing dietary NPs remains challenged due the vast number of products and the resource-intensive nature of toxicity testing. Advancements in high-throughput transcriptomics, coupled with benchmark dose (BMD) analysis are poised to modernize chemical safety assessments. The study objective was to derive transcriptomic point of departure (tPOD) values for common dietary NPs through dose-response analysis of 3'RNA-sequencing data. Two intestinal cell lines (Caco-2, HIEC-6) were exposed to 9 forms of Ag, SiO2, and TiO2, and expression of L1000 landmark genes was characterized. In Caco-2 cells, tPODmode concentrations were 0.4-0.6, 21-32, and 17-59 ppm for NPs of Ag, SiO2, and TiO2, respectively; in HIEC-6 cells, the respective tPOD values were 6-7, 7-9, and 3-13 ppm. Pathway BMDs across cases identified, for example, osteoclast and Th1/Th2 cell differentiation, and cell cycle, signaling, and senescence pathways. In all cases, the tPOD and pathway BMD values were lower than concentrations associated with cellular changes (e.g., generation of reactive oxygen species and proinflammatory cytokines, and cytotoxicity). These results demonstrate that transcriptomics dose-response analysis using in vitro models can help to increase understanding of a NP's mechanisms of action and derive quantitative information for dietary risk assessment.

Epigenetic dysregulation of enhancers in neurons is associated with Alzheimer's disease pathology and cognitive symptoms.

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.

Epigenetic Biomarkers for Parkinson's Disease: From Diagnostics to Therapeutics.

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.

Temporal control of contractile ring assembly by Plo1 regulation of myosin II recruitment by Mid1/anillin.

In eukaryotes, cytokinesis generally involves an actomyosin ring, the contraction of which promotes daughter cell segregation. Assembly of the contractile ring is tightly controlled in space and time. In the fission yeast, contractile ring components are first organized by the anillin-like protein Mid1 into medial cortical nodes. These nodes then coalesce laterally into a functional contractile ring. Although Mid1 is present at the medial cortex throughout G2, recruitment of contractile ring components to nodes starts only at mitotic onset, indicating that this event is cell-cycle regulated. Polo kinases are key temporal coordinators of mitosis and cytokinesis, and the Polo-like kinase Plo1 is known to activate Mid1 nuclear export at mitotic onset, coupling division plane specification to nuclear position. 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, and influences the timing of myosin II recruitment. Plo1 thereby facilitates contractile ring assembly at mitotic onset.