Sex-specific hippocampal 5-hydroxymethylcytosine is disrupted in response to acute stress

Papale, Ligia A.; Li, Sisi; Madrid, Andy; Zhang, Qi; Chen, Li; Chopra, Pankaj; Jin, Peng; Keleş, Sündüz; Alisch, Reid S.

doi:10.1016/j.nbd.2016.08.014

Cited by 25 publications

(23 citation statements)

References 106 publications

(142 reference statements)

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“…3b and 3c; data set 6). In fact, DE isoforms were nearly 5-times more prevalent than DE whole-genes, further supporting a role for 5hmC in RNA processing such as alternative splicing, which also is consistent with previous findings 26,32,33 . This finding prompted us to investigate whether there was an enrichment of potentially functional DhMRs at genomic structures that may facilitate alternative splicing (e.g., intron/exon boundaries).…”

Section: Resultssupporting

confidence: 88%

“…These studies parallel those of previous work that showed that acute stress disrupted 5hmC at known stress-related genes 26 . It is notable that we find an overlap of 10 potentially functional genes between both studies and that the majority of these genes are known stress-related genes [8/10 (bold): Nfia, Map3k7, Ank2, Anks1b, Dock4, Erc2, Lpin1, Ndfip2 , Nav1 , and Abca8a ].…”

Section: Discussionsupporting

confidence: 87%

“…Since we previously showed that 5hmC may regulate the expression of neuronal genes following exposure to stress by modulating the binding and/or function of transcription factors, 26 we examined whether early-life stress-related DhMRs were enriched with transcription factor (TF) binding sites using the DREME (Discriminative Regular Expression Motif Elicitation) software 37 . Forty-six TF sequence motifs (23 for hyper-DhMRs, 23 for hypo-DhMRs) significantly associated with the DhMRs (Figs.…”

Section: Resultsmentioning

confidence: 99%

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Early-life stress links 5-hydroxymethylcytosine to anxiety-related behaviors

Papale

Madrid

et al. 2017

Epigenetics

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Environmental stress contributes to the development of psychiatric disorders, including posttraumatic stress disorder and anxiety. While even acute stress alters gene expression, the molecular mechanisms underlying these changes remain largely unknown. 5-hydroxymethylcytosine (5hmC) is a novel environmentally sensitive DNA modification that is highly enriched in the brain and is associated with active transcription of neuronal genes. Here we examined behavioral and molecular alterations in adult mice that experienced an early-life stress before weaning (postnatal day 12 to 18) and found anxiety-like behaviors in adult female mice that were accompanied by correlated disruptions of hypothalamic 5hmC and gene expression in 118 genes, revealing potentially functional 5hmC (i.e., gene regulation). These genes are known and potentially novel stress-related targets, including Nr3c2, Nrxn1, Nfia, and Clip1, that have a significant enrichment for neuronal ontological functions, such as neuronal development and differentiation. Sequence motif predictions indicated that 5hmC may regulate gene expression by mediating transcription factor binding and alternative splicing of many of these transcripts. Together, these findings represent a critical step toward understanding the effects of early environment on the neuromolecular mechanisms that underlie the risk to develop anxiety disorders.

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Section: Resultssupporting

confidence: 88%

Section: Discussionsupporting

confidence: 87%

Section: Resultsmentioning

confidence: 99%

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Early-life stress links 5-hydroxymethylcytosine to anxiety-related behaviors

Papale

Madrid

et al. 2017

Epigenetics

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“…Sodium bisulfite modification cannot distinguish between 5-methyl cytosine (5-MC) and 5-hydroxy methyl cytosine (5-HMC) levels. Like 5-MC, 5-HMC can vary in the brain in response to stress [47, 48] and has been identified in various psychiatric disorders [49, 50]. Brain tissue analyses have the potential to be confounded by postmortem factors such as the method and timing of tissue preservation.…”

Section: Discussionmentioning

confidence: 99%

Discovery and replication of a peripheral tissue DNA methylation biosignature to augment a suicide prediction model

et al. 2016

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BackgroundSuicide is the second leading cause of death among adolescents in the USA, and rates are rising. Methods to identify individuals at risk are essential for implementing prevention strategies, and the development of a biomarker can potentially improve prediction of suicidal behaviors. Prediction of our previously reported SKA2 biomarker for suicide and PTSD is substantially improved by questionnaires assessing perceived stress or anxiety and is therefore reliant on psychological assessment. However, such stress-related states may also leave a biosignature that could equally improve suicide prediction. In genome-wide DNA methylation data, we observed significant overlap between waking cortisol-associated and suicide-associated DNA methylation in blood and the brain, respectively.ResultsUsing a custom bioinformatic brain to blood discovery algorithm, we derived a DNA methylation biosignature that interacts with SKA2 methylation to improve the prediction of suicidal ideation in our existing suicide prediction model across both blood and saliva data sets. This biosignature was independently validated in the Grady Trauma Project cohort and interacted with HPA axis metrics in the same cohort. The biosignature showed a relationship with immune status by its correlation with myeloid-derived cell proportions in all data sets and with IL-6 measures in a prospective postpartum depression cohort. Three probes showed significant correlations with the biosignature: cg08469255 (DDR1), cg22029879 (ARHGEF10), and cg24437859 (SHP1), of which SHP1 methylation correlated with immune measures.ConclusionsWe conclude that this biosignature interacts with SKA2 methylation to improve suicide prediction and may represent a biological state of immune and HPA axis modulation that mediates suicidal behavior.Electronic supplementary materialThe online version of this article (doi:10.1186/s13148-016-0279-1) contains supplementary material, which is available to authorized users.

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“…We also know that many risk factors for IPF are also known to change DNA methylation patterns, such as, cigarette smoke exposure [187,236], aging [34, 236,237], asbestos exposure [236,238,239], male gender [237,240], relatedness [237,241] and ethnicity [242,243].…”

Section: Chapter III Dna Methylation Of the Muc5b Promoter In Ipf Intmentioning

confidence: 99%

Regulation of MUC5B Expression in Idiopathic Pulmonary Fibrosis

Helling

Gerber

Kadiyala

et al. 2017

Am J Respir Cell Mol Biol

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Idiopathic pulmonary fibrosis (IPF) is the most common and the most aggressive fibrosing interstitial lung disease (ILD). Despite recent promising clinical trials, IPF remains incurable and largely untreatable. Genetic studies have identified several risk loci for both sporadic and familial forms of IPF. A single variant upstream of MUC5B is predicted to account for more than 30% of all IPF risk. This variant, rs35705950, is associated with expression of MUC5B in healthy lung tissue. However, the mechanism underlying the relationship between rs35705950 and MUC5B expression remains unclear.The first goal of my thesis research was to determine whether rs35705950 is also a risk factor for other forms of ILD. Genomic DNA from individuals with IPF, HP, COPD, iNSIP, and RB-ILD was obtained and genotyped for the common MUC5B promoter variant. In these populations the risk allele was associated with IPF and iNSIP which suggested a potential shared disease mechanism. Additionally, I showed that in the IPF and control populations rs35705950 is associated with lung MUC5B expression.The second goal of my thesis research was to investigate MUC5B promoter DNA methylation which has previously been shown to play a role in MUC5B expression.Methylation analysis of the 4KB region upstream of MUC5B identified two differentially methylated regions (DMRs) associated with IPF, one DMR associated with MUC5B iv expression, and one DMR associated with rs35705950. The IPF, MUC5B expression, and rs35705950 associated DMRs are all differentially methylated at a cluster of 11 CpG motifs. overlapping DMR, including the motif disrupted by rs35705950. These findings suggest that DNA methylation may play a role in MUC5B gene regulation and IPF risk.Next, I used cross species analysis to identify highly conserved domains within the overlapping DMR. Evolutionary conservation indicated selective pressures to maintain sequences overtime and suggests biological importance. The overlapping DMR contains a highly conserved binding motif for FOXA2, a transcription factor. Further analysis using ChIP-qPCR, reporter constructs, and siRNA, established a role for FOXA2 in regulation of MUC5B expression in lung tissue. Additionally, siRNA knock down identified 3 other transcription factors which are associated with MUC5B expression; STAT3, HOXA9 and ZBTB7A. These transcriptional regulators provide insight into possible therapeutic intervention for MUC5B dysregulation and IPF.The form and content of this abstract are approved. I recommend its publication.

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Sex-specific hippocampal 5-hydroxymethylcytosine is disrupted in response to acute stress

Cited by 25 publications

References 106 publications

Early-life stress links 5-hydroxymethylcytosine to anxiety-related behaviors

Early-life stress links 5-hydroxymethylcytosine to anxiety-related behaviors

Discovery and replication of a peripheral tissue DNA methylation biosignature to augment a suicide prediction model

Regulation of MUC5B Expression in Idiopathic Pulmonary Fibrosis

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