Background: Exposure to adverse environmental conditions such as toxic chemicals, viral infections, and even stress during pregnancy or early life may disrupt the development of normal brain and its functioning leading to incidence of neurodevelopmental disorders at later stages of life. Recently, we reported that poly (I:C) exposure altered synaptic plasticity protein level and impaired memory through activation of microglia cells. Purpose: As epigenetic modifications are involved in memory formation, we have studied methylation of DNA and acetylation of histone at promoters of synaptic plasticity genes in the brain of rats exposed to poly (I:C) during early life. Methods: One dose of poly (I:C) (5 mg/kg bw) was intraperitoneally injected to rat pups on postnatal seventh day. A set of pups exposed to vehicle was included as control. In order to assess methylation of DNA and acetylation of histone at synaptic plasticity gene promoter, we performed qPCR after methylated DNA immunoprecipitation and chromatin immunoprecipitation. Results: Poly (I:C) exposure reduced the level of 5-methylcytosine (5mC) at synaptic plasticity gene (bdnf, arc, and egr1) promoters in the frontal cortex (FC) and hippocampus of 3-week rats, although increased it later in both regions of 12-week rats as compared to respective controls. On contrary, poly (I:C) exposure enhanced acetylation of histone H3K9 (H3K9Ac) at promoters of these genes in both regions of 3-week rats but decreased in 12-week rats. Conclusion: Poly (I:C) exposure altered 5mC and H3K9Ac at synaptic plasticity gene promoters resulting in memory impairment of rats at later life. Keywords Poly (I:C), epigenetic modification, gene expression, DNA methylation, histone acetylation, brain development Abbreviation AD, Alzheimer’s disease; ARC, activity-regulated cytoskeleton-associated protein; BDNF, brain derived neurotrophic factor; ChIP, chromatin immunoprecipitation; DNMTs, DNA methyltransferases; EGR1, early growth response 1; FC, frontal cortex; HATs, histone acetyl transferases; HDACs, histone deacetylases; HP, hippocampus 5-mC 5-methyl cytosine; MeDIP, methylated DNA immunoprecipitation; NARP, neuro activity regulated pentaxin; PND, postnatal day; Poly (I:C), polyinosinic-polycytidylic acid; qPCR, quantitative polymerase chain reaction Introduction Department of Zoology, Banaras Hindu University, Varanasi, India. School of Studies in Neuroscience, Jiwaji University, Gwalior, India. Brain development is a tightly regulated programmed process, CSIR—Indian Institute of Toxicology Research, Lucknow, India. which includes cellular events like proliferation, migration, Corresponding author: differentiation, and synapse formation. Prenatal exposure Mahendra Kumar Thakur, Professor, Department of Zoology, Institute of to adverse environmental conditions like toxic chemicals, Science, Banaras Hindu University, Varanasi 221005, India. E-mail: firstname.lastname@example.org viral infections, and even maternal stress during pregnancy Creative Commons Non Commercial CC BY-NC: This article is distributed under the terms of the Creative Commons Attribution- NonCommercial 4.0 License (http://www.creativecommons.org/licenses/by-nc/4.0/) which permits non-Commercial use, reproduction and distribution of the work without further permission provided the original work is attributed as specified on the SAGE and Open Access pages (https://us.sagepub.com/en-us/nam/open-access-at-sage). 36 Annals of Neurosciences 26(3–4) negatively affects brain development and its function leading to neurodevelopmental disorders such as autism and schizophrenia in late life. Our previous study showed impairment of learning and memory through activation of microglia and alteration in the level of expression of synaptic plasticity related proteins (BDNF, Arc, EGR1) in the frontal cortex (FC) and hippocampus (HP) of rats exposed to poly (I:C). Highly activated microglia produce inflammatory Figure 1. Timeline of the Experiments: Exposure to Poly (I:C) Was cytokines and induce neuronal apoptosis. In addition, poly Given on PND7 and Methylation of DNA as well as Acetylation of (I:C) exposure triggers the apoptosis signaling leading Histone Were Analyzed in the Brain of 3-, 6-, and 12-week Rats to degeneration of neurons and subsequently deficits in Source: Author’s own. cognitive function including memory. On the other hand, it is reported that viral infection alters 5mC and histone Analysis of Epigenetic Modifications acetylation, which in turn affects gene expression leading to 6–9 10 neurodevelopmental disorders. Singh and Thakur have Following poly (I:C) administration, rats were sacrificed at also shown that variation in epigenetic modifications changes different age of 3-, 6-, and 12-week and FC and HP were the synaptic plasticity gene expression in cerebral cortex as isolated and used for the analysis of epigenetic modifications. well as HP of aged mice. Methylation of DNA and acetylation of histone Methylated DNA Immunoprecipitation (MeDIP) play a major role in regulation of chromatin remodeling, 11–13 The levels of 5mC at bdnf, arc, and egr1 promoters were gene expression, and memory formation. They have analyzed by MeDIP. Initially, we isolated DNA from FC also important functions in normal aging and associated and HP of control and poly (I:C) exposed rats by the phenol- neurodegenerative diseases. For DNA methylation, DNA chloroform-isoamyl alcohol (PCI) method. Then DNA was methyltransferases (DNMTs) transfer methyl groups to fifth fragmented (300–1,000bp) by sonication and quantified using carbon of cytosine at CpG sites. In case of histone acetylation, a spectrophotometer. A small fraction (20%) of fragmented histone transferases (HATs) transfer acetyl groups to histone DNA was used as input DNA control. Thereafter 4 μg tails and histone deacetylases (HDACs) remove them. fragmented DNA was diluted in 1× immunoprecipitation These epigenetic modification machineries are sensitive to medium and incubated overnight with 1 μg of 5mC antibody environmental stimulus. Earlier reports have shown that poly (A-1014; Epigentek, USA) for immunoprecipitation on ice (I:C) alters methylation of DNA and acetylation of histones in with shaking. Then, 50 μl protein A-bead was mixed and 17, 18 brain as well as immune cells. incubated on ice with shaking for 2 h. Further, the precipitated These evidences advocate that poly (I:C) exposure complex bound with beads was setteled down by centrifugation during early life might alter the expression of synaptic at 3,500 ×g at 4°C for 10 min. After careful removal of genes through modulation of epigenetic modifications and supernatant, the pellet was washed with 1× TE buffer atleast lead to memory deficits. This has prompted us to analyze three times followed by centrifugation. Finally, 200 μl elution methylation of DNA and acetylation of histone at synaptic buffer (100 mM NaHCO and 1% SDS) was added to the plasticity gene promoters in the FC as well as HP of 3-, 6-, precipitated complex, DNA was precipitated, purified, and and 12-week rats. further dissolved in equal 20 μl TE buffer for each experimental group. Thereafter, qPCR was performed using eluted and input DNA (for normalization) as template and promoter specific Methods primers to amplify specific promoter regions, 134 nucleotides of bdnf (F-5¢ -TGATCATCACTCACGACCACG-3¢ , R-5¢ - Animals and Poly (I:C) Injection CAGCCTCTCTGAGCCAGTTACG-3¢ ), 91 nucleotides of arc (F-5¢ -GGGTGGCTCTGAAGAATATTGG-3¢ , R-5¢ - Wistar rats were maintained in animal colony at School of CACCGAGCCCTGTTTGAACT-3¢ ), and 120 nucleotides Studies in Neuroscience, Jiwaji University, Gwalior. Poly of egr1 (F-5¢ -ACCACCCAACATCAGCTCTC-3¢ , R-5¢ - (I:C) was administered to rat pups on postnatal day (PND) GTGGGTGAGTGAGGAAAGGA-3¢ ). seven as described previously. All the experiments were performed according to the instructions of Committee for Chromatin Immunoprecipitation (ChIP) the Purpose of Control and Supervision of Experiments on Animals (CPCSEA), and approval of the Institutional ChIP was performed to analyze H3K9 acetylation at histone Animal Ethical Committee, Jiwaji University, Gwalior. bound to gene promoter sequence. Briefly, the FC and HP The schematic timeline for drug administration and other tissues were removed from the brain of experimental and molecular experiments is presented in Figure 1. control rats. Then tissues were chopped into small pieces Baghel et al. 37 precipitated and input fraction by the PCI method. Finally, in ice cold 1 × PBS and crosslinked with 1% formaldehyde these eluted and input DNA served as template for PCR at 25°C for 15 min. Thereafter, crosslinked tissues were amplification of gene promoter region using specific primers homogenized in lysis buffer (5 mM KOH pH 8.0, 85 mM as described above. KCl, 0.5% NP-40 with 1 mM protease inhibitors), kept at 4°C for 5 min, and spun at 1,000 × g at 4°C for 5 min. After decanting supernatant, the pellet was dissolved in Statistical Analysis nuclear lysis buffer (50 mM Tris-Cl pH 8.0, 10 mM EDTA pH 8.0, 1% SDS with 1 mM protease inhibitors) followed by The data obtained from MeDIP and ChIP qPCR assay were incubation at 4°C for 20 min and centrifugation at 12,000 × g statistically analyzed by SPSS 16.0 (Statistical Products and for 15 min to settle the debris. The chromatin complex Service Solutions, IBM Corporation, Armonk, NY, USA) present in supernatant was stored in a fresh tube and protein to check the significant mean difference between control was estimated by the Bradford method. Furthermore, we and experimental groups. The p < .05 was considered as diluted 200 μg chromatin in buffer containing 100 mM NaCl, statistically significant. Histogram was plotted with mean 20 mM Tris-Cl pH 8.0, 2 mM EDTA, pH 8.0, 1% Triton ± SEM values to display the difference between poly (I:C) X-100 with 1 mM protease inhibitors. The diluted chromatin exposed experimental and control rats. complex was incubated with protein A-sepharose beads for 2 h for preclearing step to remove non-specific binding with beads and spun at 3,500 × g for 10 min. The precleared Results supernatant was transferred to a fresh tube and divided into input (20%) and immunoprecipitation fraction (80%). The Effect on DNA Methylation immunoprecipitation fraction was incubated with H3K9Ac Alteration in 5mC level at gene promoter region tightly antibody (1 μg) overnight on ice. Then, protein A bead (50 regulates its expression. To check this, we performed MeDIP- μl) was added to it and kept for further incubation for 2 h PCR of promoter sequence of bdnf, arc, and egr1 genes. As on ice followed by centrifugation at 3,500 ×g for 10 min compared to vehicle control, a significant decrease was noted at 4°C. The supernatant was removed carefully, and pellet in 5mC level at the promoters of these genes in FC and HP was washed sequentially with different solutions (low salt, regions of poly (I:C) exposed 3- and 6-week rats; except the high salt, LiCl, and TE buffer) followed by centrifugation. arc promoter of 6-week rats which showed no difference in Thereafter, the precipitated complex was eluted with buffer methylation level. However, in poly (I:C) exposed 12-week (100 mM NaHCO and 1% SDS), mixed with 200 mM NaCl rats, 5mC level was increased in both regions as compared to and incubated at 65°C for 4 h to reverse the cross-linking control (Figure 2). of protein-DNA complex. Then DNA was isolated from the Figure 2. Analysis of Methylation Level of DNA by MeDIP-PCR at BDNF, Arc, and EGR1 Promoters in FC and HP of Postnatal 3-, 6-, and 12-week Rats. Fold Change in DNA Methylation Level of Experimental Group as Compared to Control is Shown as Mean ± SEM in the Histogram. “*” Indicates Significance in Difference (p < .05) between Poly (I:C) Exposed and Control Animals Source: Author’s own. 38 Annals of Neurosciences 26(3–4) machinery, DNA methylation is involved in the development Effect on Histone Acetylation of neural system, cognitive functions, neurodevelopmental We have also analyzed histone H3K9Ac status at the promoter 23–25 disorders and neurodegenerative diseases. Alteration in of these genes. The exposure to poly (I:C) significantly 5mC level is one of the causal factors for aging and related increased the H3K9Ac level at bdnf, arc, and egr1 promoter neurodegenerative diseases like AD. in both regions of 3-week rats. However, in 6-week, H3K9Ac We have found differential methylation pattern at the level was increased at bdnf promoter in both regions but promoter of bdnf, arc, and egr1 genes in FC as well as HP of increased at arc promoter in FC and decreased in HP. poly (I:C) exposed rats. It was initially increased in both brain Similarly, H3K9Ac at promoter of egr1 decreased in FC and regions of 3- and 6-week but later decreased in 12-week rats. In increased in HP of poly (I:C) exposed 6-week rats. Further, our previous publication, we reported that poly (I:C) injection it decreased at the promoter of these genes in both regions of activated and enhanced TNF-α positive microglia cells after 12 poly (I:C) exposed 12-week rats (Figure 3). h of exposure in hippocampus (HP) and it persisted in 3- and 12-week rats. Interestingly, TNF-α positive cells were less in number in 12-week rats as compared to early age (12 h, 3-week). Discussion Moreover, Zhao et al have shown that the treatment of TNF-α decreases methylation level at IL-32 promoter and upregulates In the current investigation, we have analyzed epigenetic its expression in cell lines. This decreased methylation continues regulation of differentially expressed synaptic plasticity upto 30 days after the withdrawal of treatment, but thereafter genes during postnatal exposure of poly (I:C) to developing it increases leading to decrease in the expression of IL-32 rats. Poly (I:C) has been reported to cause cognitive deficits expression. Thus, TNF-α level might be playing a crucial role and alterations in epigenetic modifications leading to 6, 8, 9 in decreasing DNA methylation initially in 3- and 6-week when neurological disorders. Therefore, it was likely that poly (I:C) affects the epigenetic regulation of synaptic plasticity the TNF-α level is high but increasing methylation in 12-week genes and consequently impairs memory. In epigenetic rats when the TNF-α level is relatively low. Figure 3. Analysis of Histone H3K9 Acetylation Level by ChIP-qPCR at BDNF, Arc, and EGR1 Promoters in FC and HP of Postnatal 3-, 6-, and 12-week rats. Fold Change in Acetylation Level of Experimental Group as Compared to Control is Shown as Mean ± SEM in Histogram. “*” Indicates Significance in Difference (p < .05) between Poly (I:C) Exposed and Control Animals Source: Author’s own. Baghel et al. 39 Methylation pattern also corroborates with the expression pattern of these genes. Similarly, alterations in DNA methylation and histone acetylation at bdnf, arc, egr1, homer1, and narp promoters influence their expression in the brain of aged and scopolamine-induced amnesic mice. DNA methylation recruits the suppressor complex at promoter and prevents the interaction of transcription factors, thus reducing gene transcription. DNA methylation and demethylation events are important for synaptic plasticity and memory consolidation. The inhibition of DNMT enzyme altered the level of DNA methylation and promoted the expression of synaptic plasticity reelin and bdnf genes in adult brain. Hypermethylation of bdnf promoter resulted in its downregulation in schizophrenic patients. In addition, Penner et al have shown that alterations in arc expression and its promoter methylation are associated with impairment in spatial Figure 4. Graphical Representation of Work: Exposure to Poly memory. Our results suggest that differential methylation (I:C) Enhanced Methylation of DNA and Reduced Acetylation of status at promoter affects bdnf, arc, and egr1 expression in Histones with Increasing Age Leading to Changes in Synaptic Plas- poly (I:C) induced infection. The balanced expression of ticity Gene Expression and Thereby Impairment of Memory. BDNF is critical for synaptic plasticity, synaptogenesis, Source: Author’s own. and formation of memory. Arc is an important activity dependent cytoskeleton associated protein, which helps in Acknowledgements actin polymerization, synaptogenesis, long term potentiation, This work was conducted by three research centers under a dendritic arborization, and memory consolidation. EGR1 is collaborative project supported by the Department of Biotechnology a member of immediate early gene and transcription factor, (DBT), Ministry of Science and Technology, Government of India which regulates expression of different synaptic plasticity (BT/PR14311/MED/30/470/2010). We acknowledge UGC-UPE genes. Any imbalance in the expression of these genes impairs FA-II, and Interdisciplinary School of Life Sciences for qPCR their associated functions leading to abnormal behavior and facility; UGC-CAS in Zoology, Banaras Hindu University, Varanasi cognitive functions including memory. Moreover, poly (I:C) for SRF to MSB, and DBT-BET JRF program for DBT-SRF to BS. exposure to pregnant females reduces dendritic complexity and spine density leading to cognitive impairment. Author Contributions Methylated DNA recruits HDAC2 repressor complex, MS Baghel, N Patro, VK Khanna, IK Patro, and MK Thakur: which removes acetyl group and regulates H3K9Ac level. planned and designed the experiments. Histone acetylation is crucial for memory acquisition and B Singh: Conducted poly (I:C) treatment and collected consolidation. Therefore, we have analyzed H3K9 acetylation tissue samples. level and found that in the promoter of bdnf, arc, and egr1 MS Baghel: Carried out experiments, analysed data and genes, H3K9 acetylation increased in the beginning at 3-week drafted the manuscript. and later decreased at 12-week in FC and HP of poly (I:C) VK Khanna, IK Patro, and MK Thakur: Edited the exposed rats. Acetylation level positively correlates with 3 manuscript and corresponded with the journal. the expression pattern of these genes. Poly (I:C) also alters histone acetylation by enhancing HDAC level. Moreover, Ethical Statement Fischer et al have demonstrated increase in the acetylation of H3K9 and H3K14 with enrichment of environmental The maintenance and experimental protocols were approved by factors and recovery of memory in neurodegenerative disease the Institutional Animal Ethical Committee, Jiwaji University, model. H3 and H4 acetylation also decreases at egr1, c-fos, Gwalior (Ref. no. IAEC/JU/2010/02) and carried out according 37–39 to the instructions of Committee for the Purpose of Control and and bdnf promoter in AD. Supervision of Experiments on Animals (CPCSEA). Conclusion Declaration of Conflicting Interests The authors declared no potential conflicts of interest with respect to Our findings show that the influence of poly (I:C) exposure the research, authorship and/or publication of this article. during early life also persists in later stages. The poly (I:C) exposure alters methylation of DNA and acetylation of histones Funding at synaptic plasticity gene promoters and subsequently affects gene expression in FC and HP regions of rats even at later The authors disclosed receipt of the following financial support for ages leading to impaired memory (Figure 4). the research, authorship and/or publication of this article: Department 40 Annals of Neurosciences 26(3–4) of Biotechnology (DBT), Ministry of Science and Technology, 15. Guan JS, Haggarty SJ, Giacometti E, et al. HDAC2 negatively Government of India (BT/PR14311/MED/30/470/2010). regulates memory formation and synaptic plasticity. Nature 2009; 459(7243): 55–60. References 16. Reik W. 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Annals of Neurosciences – SAGE
Published: Jul 1, 2019