Pharmacogenetic Variation in Neanderthals and Denisovans and Implications for Human Health and Response to Medications.

Modern humans carry both Neanderthal and Denisovan (archaic) genome elements that are part of the human gene pool and affect the life and health of living individuals. The impact of archaic DNA may be particularly evident in pharmacogenes-genes responsible for the processing of exogenous substances such as food, pollutants, and medications-as these can relate to changing environmental effects, and beneficial variants may have been retained as modern humans encountered new environments. However, the health implications and contribution of archaic ancestry in pharmacogenes of modern humans remain understudied. Here, we explore 11 key cytochrome P450 genes (CYP450) involved in 75% of all drug metabolizing reactions in three Neanderthal and one Denisovan individuals and examine archaic introgression in modern human populations. We infer the metabolizing efficiency of these 11 CYP450 genes in archaic individuals and find important predicted phenotypic differences relative to modern human variants. We identify several single nucleotide variants shared between archaic and modern humans in each gene, including some potentially function-altering mutations in archaic CYP450 genes, which may result in altered metabolism in living people carrying these variants. We also identified several variants in the archaic CYP450 genes that are novel and unique to archaic humans as well as one gene, CYP2B6, that shows evidence for a gene duplication found only in Neanderthals and modern Africans. Finally, we highlight CYP2A6, CYP2C9, and CYP2J2, genes which show evidence for archaic introgression into modern humans and posit evolutionary hypotheses that explain their allele frequencies in modern populations.

High-Throughput Screening of Epigenetic Inhibitors in Meningiomas Identifies HDAC, G9a, and Jumonji-Domain Inhibition as Potential Therapies.

Background Epigenetics may predict treatment sensitivity and clinical course for patients with meningiomas more accurately than histopathology. Nonetheless, targeting epigenetic mechanisms is understudied for pharmacotherapeutic development for these tumors. The bio-molecular insights and potential therapeutic development of meningioma epigenetics led us to investigate epigenetic inhibition in meningiomas. Methods We screened a 43-tumor cohort using a 139-compound epigenetic inhibitor library to assess sensitivity of relevant meningioma subgroups to epigenetic inhibition. The cohort was composed of 5 cell lines and 38 tumors cultured directly from surgery; mean patient age was 56.6 years ± 13.9 standard deviation. Tumor categories: 38 primary tumors, 5 recurrent; 33 from females, 10 from males; 32 = grade 1; 10 = grade 2; 1 = grade 3. Results Consistent with our previous results, histone deacetylase inhibitors (HDACi) were the most efficacious class. Panobinostat significantly reduced cell viability in 36 of 43 tumors; 41 tumors had significant sensitivity to some HDACi. G9a inhibition and Jumonji-domain inhibition also significantly reduced cell viability across the cohort; tumors that lost sensitivity to panobinostat maintained sensitivity to either G9a or Jumonji-domain inhibition. Sensitivity to G9a and HDAC inhibition increased with tumor grade; tumor responses did not separate by gender. Few differences were found between recurrent and primary tumors, or between those with prior radiation versus those without. Conclusions Few efforts have investigated the efficacy of targeting epigenetic mechanisms to treat meningiomas, making the clinical utility of epigenetic inhibition largely unknown. Our results suggest that epigenetic inhibition is a targetable area for meningioma pharmacotherapy.

Targeting DNA Methyl Transferases with Decitabine in Cultured Meningiomas.

OBJECTIVE: Meningiomas are a common primary central nervous system tumor that lack a U.S. Food and Drug Administration-approved pharmacotherapy. Approximately 20%-35% of meningiomas are classified as higher grade with poor outcome, whereas patients with lower-grade meningiomas are known to have long-term neurologic deficits and reduced overall survival. Recent efforts to understand the epigenetic landscape of meningiomas have highlighted the importance of DNA methylation for predicting tumor outcomes and prognosis; therefore, inhibition of these pathways may present a viable therapy for these tumors. METHODS: In this study, we perform dose-response curves of decitabine, a DNA methyltransferase inhibitor, on patient-cultured tumors and meningioma cell lines. RESULTS: Thirty total samples were evaluated, including 24 patient-cultured tumors and 6 established meningioma cell lines. Meningiomas were found to have a significant reduction in cell viability after decitabine treatment in a dose dependent manner. The effect was primarily driven by 11 of the 30 tumors in our cohort, or 36.7%. Decitabine significantly reduced cell viability across all grades, tumors from different sexes, recurrent and primary tumors, as well as tumors without a history of previous radiation. Surprisingly, our single radiation-induced tumor did demonstrate greater viability after decitabine treatment. CONCLUSIONS: Our work has identified a potential drug candidate in decitabine for the treatment of meningiomas regardless of clinical subgroup. These data require further evaluation in preclinical models, and the conclusions based on clinical subgroups need to be evaluated in a larger cohort to achieve appropriate statistical power.

High-Throughput Mechanistic Screening of Epigenetic Compounds for the Potential Treatment of Meningiomas.

BACKGROUND: Meningiomas are the most common primary central nervous system tumors. 20-30% of these tumors are considered high-grade and associated with poor prognosis and high recurrence rates. Despite the high occurrence of meningiomas, there are no FDA-approved compounds for the treatment of these tumors. METHODS: In this study, we screened patient-cultured meningiomas with an epigenetic compound library to identify targetable mechanisms for the potential treatment of these tumors. Meningioma cell cultures were generated directly from surgically resected patient tumors and were cultured on a neural matrix. Cells were treated with a library of compounds meant to target epigenetic functions. RESULTS: Although each tumor displayed a unique compound sensitivity profile, Panobinostat, LAQ824, and HC toxin were broadly effective across most tumors. These three compounds are broad-spectrum Histone Deacetylase (HDAC) inhibitors which target class I, IIa, and IIb HDACs. Panobinostat was identified as the most broadly effective compound, capable of significantly decreasing the average cell viability of the sample cohort, regardless of tumor grade, recurrence, radiation, and patient gender. CONCLUSIONS: These findings strongly suggest an important role of HDACs in meningioma biology and as a targetable mechanism. Additional validation studies are necessary to confirm these promising findings, as well to identify an ideal HDAC inhibitor candidate to develop for clinical use.

G-Quadruplexes act as sequence-dependent protein chaperones.

Maintaining proteome health is important for cell survival. Nucleic acids possess the ability to prevent protein aggregation more efficiently than traditional chaperone proteins. In this study, we explore the sequence specificity of the chaperone activity of nucleic acids. Evaluating over 500 nucleic acid sequences' effects on protein aggregation, we show that the holdase chaperone effect of nucleic acids is sequence-dependent. G-Quadruplexes prevent protein aggregation via quadruplex:protein oligomerization. They also increase the folded protein level of a biosensor in E. coli. These observations contextualize recent reports of quadruplexes playing important roles in aggregation-related diseases, such as fragile X and amyotrophic lateral sclerosis (ALS), and provide evidence that nucleic acids have the ability to modulate the folding environment of E. coli.