Authors: Giudice V, Banaszak LG, Gutierrez-Rodrigues F, Kajigaya S, Panjwani R, Fernandez Ibanez MDP, Rios O, Bleck CK, Stempinski ES, Quinones Raffo D, Townsley DM, Young NS
Journal: Haematologica. 2018 Apr 19. pii: haematol.2017.182824. doi: 10.3324/haematol.2017.182824. [Epub ahead of print]
Exosomal microRNAs modulate cancer cell metabolism and the immune response. Specific exosomal microRNAs have been reported to be reliable biomarkers of several solid and hematologic malignancies. We examined the possible diagnostic and prognostic values of exosomal microRNAs in two human bone marrow failure diseases, aplastic anemia and myelodysplastic syndromes. After screening of 372 microRNAs in a discovery set (n=42) of plasma exosome samples, we constructed a custom microRNA PCR plate, including 42 microRNAs, for validation in a larger cohort (n=99), and we identified 25 differentially expressed exosomal microRNAs uniquely or frequently present in aplastic anemia and/or myelodysplastic syndromes. These microRNAs could be related to intracellular functions, such as metabolism, cell survival, and proliferation. Clinical parameters and progression-free survival were correlated to microRNA expression levels in myelodysplastic syndromes and aplastic anemia patients before and after 6 months of immunosuppressive therapy. One microRNA, mir-126-5p, was negatively correlated with a response to therapy in aplastic anemia: patients with higher relative expression of miR-126-5p at diagnosis had the shortest progression-free survival compared to those with lower or normal levels. Our findings support the use of exosomal microRNAs in the differential diagnosis of bone marrow failure syndromes and their measurement may be useful in determining prognosis in those patients.
Authors: Kim K, Wactawski-Wende J, Michels KA, Schliep KC, Plowden TC, Chaljub EN, Mumford SL
Journal: Br J Nutr. 2018 Apr 20:1-9. doi: 10.1017/S0007114518000818. [Epub ahead of print]
Although minerals are linked to several reproductive outcomes, it is unknown whether dietary minerals are associated with ovulatory function. We hypothesised that low intakes of minerals would be associated with an increased risk of anovulation. We investigated associations between dietary mineral intake and both reproductive hormones and anovulation in healthy women in the BioCycle Study, which prospectively followed up 259 regularly menstruating women aged 18-44 years who were not taking mineral supplements for two menstrual cycles. Intakes of ten selected minerals were assessed through 24-h dietary recalls at up to four times per cycle in each participant. Oestradiol, progesterone, luteinising hormone (LH), follicle-stimulating hormone (FSH), sex-hormone-binding globulin and testosterone were measured in serum up to eight times per cycle. We used weighted linear mixed models to evaluate associations between minerals and hormones and generalised linear models for risk of anovulation. Compared with Na intake ≥1500 mg, Na intake <1500 mg was associated with higher levels of FSH (21·3%; 95% CI 7·5, 36·9) and LH (36·8 %; 95 % CI 16·5, 60·5) and lower levels of progesterone (-36·9%; 95% CI -56·5, -8·5). Na intake <1500 mg (risk ratio (RR) 2·70; 95% CI 1·00, 7·31) and Mn intake <1·8 mg (RR 2·00; 95% CI 1·02, 3·94) were associated with an increased risk of anovulation, compared with higher intakes, respectively. Other measured dietary minerals were not associated with ovulatory function. As essential minerals are mostly obtained via diet, our results comparing insufficient levels with sufficient levels highlight the need for future research on dietary nutrients and their associations with ovulatory cycles.
Authors: Tyssowski KM, DeStefino NR, Cho JH, Dunn CJ, Poston RG, Carty CE, Jones RD, Chang SM, Romeo P, Wurzelmann MK, Ward JM, Andermann ML, Saha RN, Dudek SM, Gray JM
Journal: Neuron. 2018 Apr 17. pii: S0896-6273(18)30285-X. doi: 10.1016/j.neuron.2018.04.001. [Epub ahead of print]
A vast number of different neuronal activity patterns could each induce a different set of activity-regulated genes. Mapping this coupling between activity pattern and gene induction would allow inference of a neuron's activity-pattern history from its gene expression and improve our understanding of activity-pattern-dependent synaptic plasticity. In genome-scale experiments comparing brief and sustained activity patterns, we reveal that activity-duration history can be inferred from gene expression profiles. Brief activity selectively induces a small subset of the activity-regulated gene program that corresponds to the first of three temporal waves of genes induced by sustained activity. Induction of these first-wave genes is mechanistically distinct from that of the later waves because it requires MAPK/ERK signaling but does not require de novo translation. Thus, the same mechanisms that establish the multi-wave temporal structure of gene induction also enable different gene sets to be induced by different activity durations.
Authors: Li Y, Hamilton KJ, Wang T, Coons LA, Jefferson WN, Li R, Wang Y, Grimm SA, Ramsey JT, Liu L, Gerrish KE, Williams CJ, Wade PA, Korach KS
Journal: Proc Natl Acad Sci USA. 2018 Apr 16. pii: 201719010. doi: 10.1073/pnas.1719010115. [Epub ahead of print]
Early transient developmental exposure to an endocrine active compound, diethylstilbestrol (DES), a synthetic estrogen, causes late-stage effects in the reproductive tract of adult mice. Estrogen receptor alpha (ERα) plays a role in mediating these developmental effects. However, the developmental mechanism is not well known in male tissues. Here, we present genome-wide transcriptome and DNA methylation profiling of the seminal vesicles (SVs) during normal development and after DES exposure. ERα mediates aberrations of the mRNA transcriptome in SVs of adult mice following neonatal DES exposure. This developmental exposure impacts differential diseases between male (SVs) and female (uterus) tissues when mice reach adulthood due to most DES-altered genes that appear to be tissue specific during mouse development. Certain estrogen-responsive gene changes in SVs are cell-type specific. DNA methylation dynamically changes during development in the SVs of wild-type (WT) and ERα-knockout (αERKO) mice, which increases both the loss and gain of differentially methylated regions (DMRs). There are more gains of DMRs in αERKO compared with WT. Interestingly, the methylation changes between the two genotypes are in different genomic loci. Additionally, the expression levels of a subset of DES-altered genes are associated with their DNA methylation status following developmental DES exposure. Taken together, these findings provide an important basis for understanding the molecular and cellular mechanism of endocrine-disrupting chemicals (EDCs), such as DES, during development in the male mouse tissues. This unique evidence contributes to our understanding of developmental actions of EDCs in human health.
Authors: Sorokin AV, Norris PC, English JT, Dey AK, Chaturvedi A, Baumer Y, Silverman J, Playford MP, Serhan CN, Mehta NN
Journal: J Clin Lipidol. 2018 Apr 6. pii: S1933-2874(18)30196-X. doi: 10.1016/j.jacl.2018.03.091. [Epub ahead of print]
BACKGROUND: Psoriasis (PSO) is an immune-mediated inflammatory disease associated with metabolic and cardiovascular comorbidities. It is now known that resolution of inflammation is an active process locally controlled by specialized proresolving mediators (SPMs), named resolvins (Rvs), protectins, and maresins.
OBJECTIVE: It is unknown whether these potent lipid mediators (LMs) are involved in PSO pathophysiology and if the skin and blood have disease-specific SPMs phenotype profiles.
METHODS: We used liquid chromatography-tandem mass spectrometry-based LM metabololipidomics to obtain skin and peripheral blood LM profiles from PSO compared to healthy subjects. Some LMs were tested in cell culture experiments with corresponding gene expression and protein concentration analyses.
RESULTS: The levels of several LM were significantly elevated in lesional PSO skin compared to nonlesional and skin from healthy subjects. Particularly, RvD5, protectins Dx, and aspirin-triggered forms of lipoxin were present only in lesional PSO skin, whereas protectin D1 was present in nonlesional PSO skin. To determine specific roles of SPMs on skin-related inflammatory cytokines, RvD1 and RvD5 were incubated with human keratinocytes. RvD1 and RvD5 reduced the expression levels of interleukin 24 and S100A12, whereas only RvD1 significantly abrogated interleukin-24 production by keratinocytes.
CONCLUSIONS: These findings suggest that an imbalance between locally produced proresolution and proinflammatory LMs identified in PSO skin and blood compartments might play a role in PSO pathophysiology. Moreover, some of the PSO-related cytokines can be modified by specific SPMs and involved mechanisms support investigation of targeting novel proresolving lipid mediators as a therapy for PSO.
Authors: Jian X, Felsenfeld G
Journal: Proc Natl Acad Sci USA. 2018 Apr 30. pii: 201803146. doi: 10.1073/pnas.1803146115. [Epub ahead of print]
Both type 1 and type 2 diabetes involve a complex interplay between genetic, epigenetic, and environmental factors. Our laboratory has been interested in the physical interactions, in nuclei of human pancreatic β cells, between the insulin (INS) gene and other genes that are involved in insulin metabolism. We have identified, using Circularized Chromosome Conformation Capture (4C), many physical contacts in a human pancreatic β cell line between the INS promoter on chromosome 11 and sites on most other chromosomes. Many of these contacts are associated with type 1 or type 2 diabetes susceptibility loci. To determine whether physical contact is correlated with an ability of the INS locus to affect expression of these genes, we knock down INS expression by targeting the promoter; 259 genes are either up or down-regulated. Of these, 46 make physical contact with INS. We analyze a subset of the contacted genes and show that all are associated with acetylation of histone H3 lysine 27, a marker of actively expressed genes. To demonstrate the usefulness of this approach in revealing regulatory pathways, we identify from among the contacted sites the previously uncharacterized gene SSTR5-AS1 and show that it plays an important role in controlling the effect of somatostatin-28 on insulin secretion. These results are consistent with models in which clustering of genes supports transcriptional activity. This may be a particularly important mechanism in pancreatic β cells and in other cells where a small subset of genes is expressed at high levels.
Authors: Reed JL, D'Ambrosio E, Marenco S, Ursini G, Zheutlin AB, Blasi G, Spencer BE, Romano R, Hochheiser J, Reifman A, Sturm J, Berman KF, Bertolino A, Weinberger DR, Callicott JH.
Journal: PLoS One. 2018 Apr 10;13(4):e0195189. doi: 10.1371/journal.pone.0195189.
Brain phenotypes showing environmental influence may help clarify unexplained associations between urban exposure and psychiatric risk. Heritable prefrontal fMRI activation during working memory (WM) is such a phenotype. We hypothesized that urban upbringing (childhood urbanicity) would alter this phenotype and interact with dopamine genes that regulate prefrontal function during WM. Further, dopamine has been hypothesized to mediate urban-associated factors like social stress. WM-related prefrontal function was tested for main effects of urbanicity, main effects of three dopamine genes-catechol-O-methyltransferase (COMT), dopamine receptor D1 (DRD1), and dopamine receptor D2 (DRD2)-and, importantly, dopamine gene-by-urbanicity interactions. For COMT, three independent human samples were recruited (total n = 487). We also studied 253 subjects genotyped for DRD1 and DRD2. 3T fMRI activation during the N-back WM task was the dependent variable, while childhood urbanicity, dopamine genotype, and urbanicity-dopamine interactions were independent variables. Main effects of dopamine genes and of urbanicity were found. Individuals raised in an urban environment showed altered prefrontal activation relative to those raised in rural or town settings. For each gene, dopamine genotype-by-urbanicity interactions were shown in prefrontal cortex-COMT replicated twice in two independent samples. An urban childhood upbringing altered prefrontal function and interacted with each gene to alter genotype-phenotype relationships. Gene-environment interactions between multiple dopamine genes and urban upbringing suggest that neural effects of developmental environmental exposure could mediate, at least partially, increased risk for psychiatric illness in urban environments via dopamine genes expressed into adulthood.
Authors: Lozoya OA, Martinez-Reyes I, Wang T, Grenet D, Bushel P, Li J, Chandel N, Woychik RP, Santos JH
Journal: PLoS Biol. 2018 Apr 18;16(4):e2005707. doi: 10.1371/journal.pbio.2005707. [Epub ahead of print]
Mitochondrial function affects many aspects of cellular physiology, and, most recently, its role in epigenetics has been reported. Mechanistically, how mitochondrial function alters DNA methylation patterns in the nucleus remains ill defined. Using a cell culture model of induced mitochondrial DNA (mtDNA) depletion, in this study we show that progressive mitochondrial dysfunction leads to an early transcriptional and metabolic program centered on the metabolism of various amino acids, including those involved in the methionine cycle. We find that this program also increases DNA methylation, which occurs primarily in the genes that are differentially expressed. Maintenance of mitochondrial nicotinamide adenine dinucleotide reduced (NADH) oxidation in the context of mtDNA loss rescues methionine salvage and polyamine synthesis and prevents changes in DNA methylation and gene expression but does not affect serine/folate metabolism or transsulfuration. This work provides a novel mechanistic link between mitochondrial function and epigenetic regulation of gene expression that involves polyamine and methionine metabolism responding to changes in the tricarboxylic acid (TCA) cycle. Given the implications of these findings, future studies across different physiological contexts and in vivo are warranted.
Authors: Diaz-Ruiz A, Lanasa M, Garcia J, Mora H, Fan F, Martin-Montalvo A, Di Francesco A, Calvo-Rubio M, Salvador-Pascual A, Aon MA, Fishbein KW, Pearson KJ, Villalba JM, Navas P, Bernier M, de Cabo R
Journal: Aging Cell. 2018 Apr 28:e12767. doi: 10.1111/acel.12767. [Epub ahead of print]
Calorie restriction (CR) is one of the most robust means to improve health and survival in model organisms. CR imposes a metabolic program that leads to increased stress resistance and delayed onset of chronic diseases, including cancer. In rodents, CR induces the upregulation of two NADH-dehydrogenases, namely NAD(P)H:quinone oxidoreductase 1 (Nqo1) and cytochrome b5 reductase 3 (Cyb5r3), which provide electrons for energy metabolism. It has been proposed that this upregulation may be responsible for some of the beneficial effects of CR, and defects in their activity are linked to aging and several age-associated diseases. However, it is unclear whether changes in metabolic homeostasis solely through upregulation of these NADH-dehydrogenases have a positive impact on health and survival. We generated a mouse that overexpresses both metabolic enzymes leading to phenotypes that resemble aspects of CR including a modest increase in lifespan, greater physical performance, a decrease in chronic inflammation, and, importantly, protection against carcinogenesis, one of the main hallmarks of CR. Furthermore, these animals showed an enhancement of metabolic flexibility and a significant upregulation of the NAD+/sirtuin pathway. The results highlight the importance of these NAD+ producers for the promotion of health and extended lifespan.
Authors: Mischkowski D, Palacios-Barrios EE, Banker L, Dildine TC, Atlas LY
Journal: Pain. 2018 Apr;159(4):699-711. doi: 10.1097/j.pain.0000000000001132.
Nociception reliably elicits an autonomic nervous system (ANS) response. Because pain and ANS circuitry interact on multiple spinal, subcortical, and cortical levels, it remains unclear whether autonomic responses are simply a reflexive product of noxious stimulation regardless of how stimulation is consciously perceived or whether the experience of pain mediates ANS responses to noxious stimulation. To test these alternative predictions, we examined the relative contribution of noxious stimulation and individual pain experience to ANS responses in healthy volunteers who underwent 1 or 2 pain assessment tasks. Participants received 8 seconds of thermal stimulation of varied temperatures and judged pain intensity on every trial. Skin conductance responses and pupil dilation responses to stimulation served as measures of the heat-evoked autonomic response. We used multilevel modelling to examine trial-by-trial relationships between heat, pain, and ANS response. Although both pain and noxious heat stimulation predicted skin conductance response and pupil dilation response in separate analyses, the individual pain experience statistically mediated effects of noxious heat on both outcomes. Furthermore, moderated mediation revealed that evidence for this process was stronger when stimulation was perceived as painful compared with when stimulation was perceived as nonpainful. These findings suggest that pain appraisal regulates the heat-evoked autonomic response to noxious stimulation, documenting the flexibility of the autonomic pain response to adjust to perceived or actual changes in environmental affordances above and beyond nociceptive input.