RNA transcript is critical to regulating gene associated with Alzheimer’s disease

Researchers funded by NIEHS determined that an RNA transcript called AANCR is pivotal to regulating expression of the APOE gene implicated in Alzheimer’s disease. The findings could inform development of therapeutic targets for neurodegenerative diseases.

Human DNA contains sections called enhancers that are involved in regulating complex patterns of gene expression. When those sections are transcribed, or copied, into RNA, the resulting transcript is called enhancer RNA. Most enhancer RNAs promote transcription of genes brought together through chromatin loops, structures that form when a chromosome bends back on itself. Variation in enhancers can influence susceptibility to diseases.

Previously, the researchers found that an enhancer RNA called AANCR influences APOE activity. For this study, they examined whether the mere process of AANCR transcription or the transcript itself was necessary for APOE expression. Using nervous system cells, they measured how APOE levels responded when AANCR transcription was prevented or when transcripts were degraded. In addition, they used fluorescent tags to observe proximity between AANCR transcripts and the APOE gene. Through another series of experiments, they examined how AANCR is activated and its ties to neuroinflammation.

Expression of APOE decreased with declining AANCR transcript levels. The imaging study also showed AANCR transcripts located near the APOE gene. In addition, the team identified a pathway that promoted AANCR transcription, which was associated with an inflammatory response in nervous system cells.

According to the authors, the findings indicate that AANCR is a key enhancer RNA for regulating APOE expression and influencing inflammatory response in the nervous system. They added that AANCR could be a potential target for treating neurodegenerative diseases and neuroinflammation, but more research is necessary to understand how it regulates APOE.

Citation: Wan M, Liu Y, Li D, Snyder RJ, Elkin LB, Day CR, Rodriguez J, Grunseich C, Mahley RW, Watts JA, Cheung VG. 2024. The enhancer RNA, AANCR, regulates APOE expression in astrocytes and microglia. Nucleic Acids Res 52(17):10235-54.

Giant proteins involved in algal toxin synthesis discovered

Researchers have discovered two massive proteins essential to the structure of an algal toxin responsible for large fish kills. The NIEHS-funded work addresses a long-standing question about how certain algae make their toxins.

Harmful algal blooms are global threats to public health, ecosystems, and food security. Toxins called prymnesins, produced by the algal species Prymnesium parvum, destroy red blood cells necessary for fish to breathe. Although prymnesins — part of a class of natural toxins called marine polyethers — are among the largest biological compounds known, how algae produce them has been a mystery. Their chemical structure suggests that algae first synthesize precursor molecules that fuse together to form a ladder-like structure.

Building on previous work that mapped P. parvum DNA, the team catalogued genes potentially involved in prymnesin production. By consulting a database of known polyketide genes, they focused on several large, contiguous “hot spots” of P. parvum DNA that stood out. Using a manual process, they predicted that these hot spots were composed of single massive genes. Through RNA, protein, and chemical analyses, they determined whether the proposed genes could make prymnesin precursors.

The team determined that two giant genes, PKZILLA-1 and PKZILLA-2, produce proteins that likely join to generate the tell-tale ladder frame of the pyrmnesin molecule. PKZILLA-1 is about 25% bigger than the largest protein found in humans, a muscle protein called titin.

According to the researchers, the findings provide a model for studying other marine algal genes and associated toxins that are harmful to human health. By using omics approaches — which blend data from different fields of biology — the work also expands understanding of genetic and protein size limits in biology.

Citation: Fallon TR, Shende VV, Wierzbicki IH, Pendleton AL, Watervoort NF, Auber RP, Gonzalez DJ, Wisecaver JH, Moore BS. 2024. Giant polyketide synthase enzymes in the biosynthesis of giant marine polyether toxins. Science 385(6709):671-8.

Mechanism underlying pregnancy complications from benzene exposure identified

NIEHS-funded researchers identified a molecular mechanism by which benzene disrupts embryo implantation. The findings shed light on how air pollution exposure can lead to pregnancy complications.

Embryo implantation is tightly regulated. After attachment of the blastocyst — a cluster of cells forming an early-stage embryo — to the inner lining of the uterus, cells called trophoblasts migrate from the blastocyst to the uterine lining through a process called invasion. Errors in migration or invasion will lead to embryo implantation failure or miscarriage. Exposure to air pollutants such as benzene can cause pregnancy complications, but little is known about the underlying mechanisms.

The researchers focused on the effect of hydroquinone, a benzene metabolite, on trophoblast function. First, they treated trophoblast cells with hydroquinone at two different concentrations. Using those cells, they created 3D blastocyst models and applied imaging techniques to examine trophoblast migration and invasion. Finally, they analyzed how hydroquinone exposure affected gene expression in trophoblasts.

Trophoblast migration and invasion decreased with increasing concentrations of hydroquinone. Genetic analysis showed that hydroquinone reduced activity of Twist1, a gene reportedly under-expressed in miscarriages, as well as IFITM1, a gene implicated in metastatic cancer. Silencing Twist1 caused IFITM1 expression to decline, indicating that Twist1 regulates IFITM1. The team also found that deactivating the aryl hydrocarbon receptor (AhR) pathway — which mediates the toxic effects of chemicals — increased Twist1 and IFITM1 expression in the presence of hydroquinone.

According to the authors, the results suggest that benzene exposure affects an AhR-Twist1-IFITM1 pathway critical to regulating trophoblast migration and invasion. By providing insight into the effects of benzene exposure on pregnancy, the study could inform preventive strategies to reduce exposures.

Citation: Maxwell A, Swanson G, Thy Nguyen A, Hu A, Richards D, You Y, Stephan L, Manaloto M, Liao A, Ding J, Mor G. 2024. Hydroquinone impairs trophoblast migration and invasion via AHR-twist-IFITM1 axis. Placenta 155:88-99.

Long-term study assesses drinking water quality and potential health risks post-Hurricane Maria

Tap water quality in Puerto Rico showed partial recovery starting six months after Hurricane Maria, according to NIEHS-funded researchers. The study provides the first long-term, island-wide assessment of changes in drinking water quality following the storm.

Flooding and damage from Hurricane Maria in September 2017 worsened existing drinking water contamination in Puerto Rico. Previous research indicated an overall increase in drinking water contaminant levels from December 2017 to February 2018. For this study, the researchers sought to understand the longer term effects of Maria on water quality and the potential associated health risks.

From March to November 2018, the team collected 59 tap water samples from 16 municipalities across Puerto Rico, including from participants in the PROTECT cohort, funded by the NIEHS Superfund Research Program. The researchers analyzed the samples for 200 organic pollutants and 22 trace elements. In addition, they tested the samples for toxic effects using yeast cells and human lung cells.

They detected all trace elements and 19% of the organic pollutants at least once at concentrations below federally recommended health-based limits. Average concentrations of 11 trace elements and seven organic pollutants decreased during the study period compared with previously measured levels, indicating that Hurricane Maria had a strong but temporary impact on tap water. However, levels of seven other trace elements and 10 different organic pollutants increased, suggesting continuing sources of input.

According to the authors, the most common pollutants identified — copper, strontium, vanadium, and perfluorooctanoic acid — could potentially contribute to adverse health outcomes such as inflammation, impaired reproductive systems, cancers, or organ toxicity.

The authors noted the results emphasize the importance of continued drinking water monitoring, especially in risk-prone areas. More health-based epidemiological data could help improve water resource management and quality control in Puerto Rico.

Citation: Lin Y, Li G, Rivera MS, Jiang T, Cotto I, Carpenter CMG, Rich SL, Giese RW, Helbling DE, Padilla IY, Rosario-Pabón Z, Alshawabkeh AN, Pinto A, Gu AZ. 2024. Long-term impact of Hurricane Maria on point-of-use drinking water quality in Puerto Rico and associated potential adverse health effects. Water Res 265:122213.