Functional annotation of the human brain methylome identifies tissue-specific epigenetic variation across brain and blood

Background

Dynamic changes to the epigenome play a critical role in establishing and maintaining cellular phenotype during differentiation, but little is known about the normal methylomic differences that occur between functionally distinct areas of the brain. We characterized intra- and inter-individual methylomic variation across whole blood and multiple regions of the brain from multiple donors.

Results

Distinct tissue-specific patterns of DNA methylation were identified, with a highly significant over-representation of tissue-specific differentially methylated regions (TS-DMRs) observed at intragenic CpG islands and low CG density promoters. A large proportion of TS-DMRs were located near genes that are differentially expressed across brain regions. TS-DMRs were significantly enriched near genes involved in functional pathways related to neurodevelopment and neuronal differentiation, including BDNF, BMP4, CACNA1A, CACA1AF, EOMES, NGFR, NUMBL, PCDH9, SLIT1, SLITRK1 and SHANK3. Although between-tissue variation in DNA methylation was found to greatly exceed between-individual differences within any one tissue, we found that some inter-individual variation was reflected across brain and blood, indicating that peripheral tissues may have some utility in epidemiological studies of complex neurobiological phenotypes.

Conclusions

This study reinforces the importance of DNA methylation in regulating cellular phenotype across tissues, and highlights genomic patterns of epigenetic variation across functionally distinct regions of the brain, providing a resource for the epigenetics and neuroscience research communities.     

Epigenetic and genetic variation at the IGF2/H19 imprinting control region on 11p15.5 is associated with cerebellum weight

IGF2 is a paternally expressed imprinted gene with an important role in development and brain function. Allele-specific expression of IGF2 is regulated by DNA methylation at three differentially methylated regions (DMRs) spanning the IGF2/H19 domain on human 11p15.5. We have comprehensively assessed DNA methylation and genotype across the three DMRs and the H19 promoter using tissue from a unique collection of well-characterized and neuropathologically-dissected post-mortem human cerebellum samples (n = 106) and frontal cortex samples (n = 51). We show that DNA methylation, particularly in the vicinity of a key CTCF-binding site (CTCF3) in the imprinting control region (ICR) upstream of H19, is strongly correlated with cerebellum weight. DNA methylation at CTCF3 uniquely explains ∼25% of the variance in cerebellum weight. In addition, we report that genetic variation in this ICR is strongly associated with cerebellum weight in a parental-origin specific manner, with maternally-inherited alleles associated with a 16% increase in cerebellum weight compared with paternally-inherited alleles. Given the link between structural brain abnormalities and neuropsychiatric disease, an understanding of the epigenetic and parent-of-origin specific genetic factors associated with brain morphology provides important clues about the etiology of disorders such as schizophrenia and autism.Key words: epigenetic, DNA methylation, genomic imprinting, cerebellum, IGF2, H19, brain, expression, frontal cortex, genetic, single nucleotide polymorphism     

Involvement of Zn Depletion in Cd-Induced Toxicity on Prenatal Bone Formation in Rat

This experiment was conducted to evaluate the effects of chromium methionine with/without zinc sulfate or zinc amino acid complex on the growth performance, carcass traits, meat quality, serum parameters, endocrine parameters, and antioxidant status of growing-finishing pigs. A total of 180 (32.0 ± 1.7 kg body weight, BW) crossbred pigs (Duroc × Landrace × Yorkshire) were used in a completely randomized design with three dietary treatments and 10 replicates per treatment (five pens of barrows and five pens of gilts with six pigs per replicate). Three treatments were corn-soybean meal-based diets supplemented with 100 mg Zn/kg from zinc sulfate (ZnSO₄), 100 mg Zn/kg from ZnSO₄ + 0.2 mg Cr/kg from chromium methionine complex (CrMet), or 50 mg Zn/kg from ZnSO₄ + 50 mg Zn/kg from zinc amino acid complex (ZnAA) + 0.2 mg Cr/kg from CrMet, respectively. The experiment lasted 105 days, of which was divided into three stages including phase 1 (30 to 50 kg BW), phase 2 (50 to 80 kg BW), and phase 3 (80 to 110 kg BW). Results showed that supplementation with CrMet and ZnAA improved (P < 0.05) the feed conversion of the pigs in phase 2, phase 3, and the overall experiment. Hot carcass weight, dressing percentage, and a longissimus dorsi muscle area were increased (P < 0.05) in pigs fed with diets supplemented with both CrMet and ZnAA compared with pigs fed with diets containing only ZnSO₄ (P < 0.05). There was also an increase (P < 0.01) pH_24 h in the longissimus dorsi muscle in pigs fed with diets supplemented with CrMet and ZnAA. The concentration of serum glucose in pigs fed with diets containing CrMet and ZnAA was decreased (P < 0.05) compared with that in pigs fed with the diet containing ZnSO₄. Supplementation with CrMet and ZnAA increased (P < 0.05) the circulating levels of insulin and decreased (P < 0.05) cortisol. There was an increase (P < 0.05) in total serum antioxidant capacity and Cu/Zn superoxide dismutase activity as well as a decrease (P < 0.05) in serum malondialdehyde concentrations in pigs fed with diets supplemented with CrMet and ZnAA compared with pigs fed with the diet supplemented only with ZnSO₄. In conclusion, supplementation of CrMet only or CrMet together with ZnAA improved feed conversion, carcass traits, and meat quality in the growing-finishing pigs.     

Potato dehydrins present high intrinsic disorder and are differentially expressed under ABA and abiotic stresses

Dehydrins (DHNs) correspond to late embryogenesis abundant proteins (LEA) of group 2, they are known as glycin rich proteins. Despite their expression during the late seed maturation stages, they are also involved in plant response to a number of abiotic stresses such as drought, salinity and cold. In the present study, we identified five full-length cDNAs encoding dehydrins (designated StDHN2a, StDHN1, TAS14, StDHN25 and StLEA27) isolated from potato. These dehydrins were composed of serine amino acids called S domain and lysine-rich segment corresponding to a K domain. Three DHNs (StDHN1, TAS14 and StLEA27) contained Y segments. In silico analysis showed that these StDHN sequences share high homology with other Solanum dehydrin proteins species. The analysis of gene expression using quantitative RT-PCR showed that they were upregulated by dehydration and salinity. Moreover, the search for putative regulatory element in the promoter sequence of dehydrin genes was investigated.     

Biosorption of a textile dye (Acid Blue 40) by cone biomass of Thuja orientalis: estimation of equilibrium, thermodynamic and kinetic parameters

Biosorption of Acid Blue 40 (AB40) onto cone biomass of Thuja orientalis was studied with variation in the parameters of pH, contact time, biosorbent and dye concentration and temperature to estimate the equilibrium, thermodynamic and kinetic parameters. The AB40 biosorption was fast and the equilibrium was attained within 50 min. Equilibrium data fitted well to the Langmuir isotherm model in the studied concentration range of AB40 and at various temperatures. Maximum biosorption capacity (q(max)) for AB40 was 2.05 x 10(-4)mol g(-1) or 97.06 mg g(-1) at 20 degrees C. The changes of Gibbs free energy, enthalpy and entropy of biosorption were also evaluated for the biosorption of AB40 onto T. orientalis. The results indicate that the biosorption was spontaneous and exothermic. Kinetics of biosorption of AB40 was analyzed and rate constants were also derived and the results show that the pseudo-second-order kinetic model agrees very well with the experimental data.     

Granzyme a, a stealth killer in the mitochondrion

The induction of caspase-independent cell death by killer lymphocytes involves the serine protease granzyme A (GzmA). In this issue, Martinvalet et al. (2008) show that GzmA penetrates the mitochondrial matrix without perturbing normal mitochondrial functions. In the mitochondrial matrix, GzmA cleaves NDUFS3 (a component of the electron transport chain) leading to production of reactive oxygen species and ultimately to cell death.     

Lipid oxidation enhances the function of activated protein C

Although lipid oxidation products are usually associated with tissue injury, it is now recognized that they can also contribute to cell activation and elicit anti-inflammatory lipid mediators. In this study, we report that membrane phospholipid oxidation can modulate the hemostatic balance. Oxidation of natural phospholipids results in an increased ability of the membrane surface to support the function of the natural anticoagulant, activated protein C (APC), without significantly altering the ability to support thrombin generation. Lipid oxidation also potentiated the ability of protein S to enhance APC-mediated factor Va inactivation. Phosphatidylethanolamine, phosphatidylserine, and polyunsaturation of the fatty acids were all required for the oxidation-dependent enhancement of APC function. A subgroup of thrombotic patients with anti-phospholipid antibodies specifically blocked the oxidation-dependent enhancement of APC function. Since leukocytes are recruited and activated at the thrombus or sites of vessel injury, our findings suggest that after the initial thrombus formation, lipid oxidation can remodel the membrane surface resulting in increased anticoagulant function, thereby reducing the thrombogenicity of the thrombus or injured vessel surface. Anti-phospholipid antibodies that block this process would therefore be expected to contribute to thrombus growth and disease.     

Ectopic expression of a grape vine vacuolar NHX antiporter enhances transgenic potato plant tolerance to salinity

Journal of Plant Biochemistry and Biotechnology - Salinity is a crucial environmental constraint that reduces plant productivity. However, plants activate different signaling pathways to overcome...