FKBP5 Research Articles

Deep phenotyping reveals CRH and FKBP51-dependent behavioral profiles following chronic social stress exposure in male mice.

The co-chaperone FKBP51, encoded by FKBP5 gene, is recognized as a psychiatric risk factor for anxiety and depressive disorders due to its crucial role in the stress response. Another key modulator in stress response regulation is the corticotropin releasing hormone (CRH), which is co-expressed with FKBP51 in many stress-relevant brain-regions and cell-types. Together, they intricately influence the balance of the hypothalamic-pituitary-adrenal (HPA) axis, one of the primary stress response systems. Previous research underscores the potential moderating effects these genes have on the regulation of the stressful life events towards the vulnerability of major depressive disorder (MDD). However, the specific function of FKBP51 in CRH-expressing neurons remains largely unexplored. Here, through deep behavioral phenotyping, we reveal heightened stress effects in mice lacking FKBP51 in CRH co-expressing neurons (CRHFKBP5-/-), particularly evident in social contexts. Our findings highlight the importance of considering cell-type specificity and context in comprehending stress responses and advocate for the utilization of machine-learning-driven phenotyping of mouse models. By elucidating these intricacies, we lay down the groundwork for personalized interventions aimed at enhancing stress resilience and individual well-being.

Personality vulnerability to depression, resilience, and depressive symptoms: epigenetic markers among perinatal women.

We examined differences in DNA methylation patterns in the NR3C1 and FKBP5 genes in relation to personality vulnerability to depression, resilience, and perinatal depressive symptoms, whilst also considering possible moderating effects of childhood traumatic events. N = 160 perinatal women were assessed at late pregnancy and 1 year postpartum for personality vulnerability to depression, resilience, depressive symptoms, and childhood traumatic events with self-reported questionnaires. NR3C1 and FKBP5 methylation markers were analyzed via sodium bisulfite sequencing. Associations of methylation markers with the above mentioned variables were tested using multivariable regressions. NR3C1 methylation at CpGs 1, 4 and average methylation sites were negatively associated with resilience; NR3C1 methylation at CpG 2 was positively associated with postpartum depressive symptoms; methylation at CpG 4 was positively associated with prenatal depressive symptoms. The interaction between current distress due to interpersonal traumatic events and NR3C1 CpG sites in relation to personality vulnerability was significant on CpG sites 3 and 4, whereas the interaction between current distress due to total traumatic events and NR3C1 in relation to personality vulnerability was significant on CpG site 2. FKBP5 showed no significant associations with the outcomes. This study identified associations between NR3C1 methylation and resilience as well as perinatal depressive symptoms. Interestingly, an interaction between early trauma and personality vulnerability was noted. Our findings on these specific DNA methylation markers may, if replicated and integrated into risk prediction models, contribute to early diagnosis of mothers at risk, targeted health promotion, and early interventions.

Fkbp5 gene deletion: Circadian rhythm profile and brain proteomics in aged mice.

FKBP51, also known as FK506-binding protein 51, is a molecular chaperone and scaffolding protein with significant roles in regulating hormone signaling and responding to stress. Genetic variants in FKBP5, which encodes FKBP51, have been implicated in a growing number of neuropsychiatric disorders, which has spurred efforts to target FKBP51 therapeutically. However, the molecular mechanisms and sub-anatomical regions influenced by FKBP51 in these disorders are not fully understood. In this study, we aimed to examine the impact of Fkbp5 ablation using circadian phenotyping and molecular analyses. Our findings revealed that the lack of FKBP51 did not significantly alter circadian rhythms, as detected by wheel-running activity, but did offer protection against stress-mediated disruptions in rhythmicity in a sex-dependent manner. Protein changes in Fkbp5 KO mice, as measured by histology and proteomics, revealed alterations in a brain region- and sex-dependent manner. Notably, regardless of sex, aged Fkbp5 KOs showed elevated MYCBP2, FBXO45, and SPRYD3 levels, which are associated with neuronal-cell adhesion and synaptic integrity. Additionally, pathways such as serotonin receptor signaling and S100 family signaling were differentially regulated in Fkbp5 KO mice. Weighted protein correlation network analysis identified protein networks linked with synaptic transmission and neuroinflammation. The information generated by this work can be used to better understand the molecular changes in the brain during aging and in the absence of Fkbp5, which has implications for the continued development of FKBP51-focused therapeutics for stress-related disorders.

Muscle growth differences in Lijiang pigs revealed by ATAC-seq multi-omics.

As one of the largest tissues in the animal body, skeletal muscle plays a pivotal role in the production and quality of pork. Consequently, it is of paramount importance to investigate the growth and developmental processes of skeletal muscle. Lijiang pigs, which naturally have two subtypes, fast-growing and slow-growing, provide an ideal model for such studies by eliminating breed-related influences. In this study, we selected three fast-growing and three slow-growing 6-month-old Lijiang pigs as subjects. We utilized assay for transposase-accessible chromatin with sequencing (ATAC-seq) combined with genomics, RNA sequencing, and proteomics to screen for differentially expressed genes and transcription factors linked to increased longissimus dorsi muscle volume in Lijiang pigs. We identified 126 genes through ATAC-seq, including PPARA, TNRC6B, NEDD1, and FKBP5, that exhibited differential expression patterns during muscle growth. Additionally, we identified 59 transcription factors, including Foxh1, JunB, Mef2 family members (Mef2a/b/c/d), NeuroD1, and TEAD4. By examining open chromatin regions (OCRs) with significant genetic differentiation, genes such as SAV1, CACNA1H, PRKCG, and FGFR4 were found. Integrating ATAC-seq with transcriptomics and transcriptomics with proteomics, we identified differences in open chromatin regions, transcription, and protein levels of FKBP5 and SCARB2 genes in fast-growing and slow-growing Lijiang pigs. Utilizing multi-omics analysis with R packages, we jointed ATAC-seq, transcriptome, and proteome datasets, identifying enriched pathways related to glycogen metabolism and skeletal muscle cell differentiation. We pinpointed genes such as MYF6 and HABP2 that exhibit strong correlations across these diverse data types. This study provides a multi-faceted understanding of the molecular mechanisms that lead to differences in pig muscle fiber growth.

The role of CRHR1 and FKBP5 genes in juvenile delinquency among children aged between 12 and 18 years: a case–control study

ABSTRACT Juvenile delinquency, where young people engage in criminal behavior, is a serious concern for society due to high arrest rates among minors. Delinquent behavior is a serious concern due to its devastating effect on the well-being of society. The relationship between genetics and violent behavior is complex and not fully understood. This study aims to investigate the correlation between specific genetic traits, particularly CRHR1 and FKBP5 genes, and sociodemographic characteristics in the context of their age, gender, socioeconomic status, and crime history of delinquent behavior in adolescents. The study was designed as a single-center hospital-based case–control study involving 45 adolescents for each study group: control and those showing delinquent behavior, case group. Findings revealed an abnormal CRHR1 expression in male teenagers is a strong indicator and presents the risk for violent and delinquent behavior. Understanding specific genetic markers, like abnormal CRHR1 expression, helps target assessments and interventions. Additionally, recognizing sociodemographic factors associated with delinquency allows for a more comprehensive approach, considering the various influences on adolescent behavior. This study provides important insights to address and reduce the complex issue of juvenile delinquency.

Effects of improved on-farm crop storage on DNA methylation of mothers and their infants: evidence from a randomized controlled trial in Kenya

BackgroundStress during pregnancy can lead to adverse maternal and infant health outcomes through epigenetic changes in the hypothalamic–pituitary–adrenal axis. Among farmers in low-income countries, one important stressor is food insecurity, which can be reduced using hermetic storage bags. This study aimed to determine, for the first time, whether a hermetic storage bag intervention during pregnancy positively affects maternal and infant DNA methylation of the hypothalamic–pituitary–adrenal axis-related genes FKBP5 and NR3C1. We further analyzed whether anthropometrics, stress, and mental health were associated with DNA methylation.MethodsThis study was part of a larger matched-pair randomized controlled trial focusing on the impact of improved on-farm storage on food security, poverty, and net income of smallholder farming households. A total of N = 149 mothers were recruited by telephone and invited to attend a study appointment at health facilities in Kakamega County, Western Kenya, with their infants in April or May 2021. During the appointment, anthropometric measurements were taken, questionnaires on stress and mental health were administered, and saliva samples were collected. Logistic and multiple linear regression were used to examine the effect of the intervention and related measures on DNA methylation.ResultsMothers in the intervention group showed higher mean NR3C1 methylation levels than those in the control group, corrected for multiple testing. Maternal postpartum body mass index was positively associated with infant NR3C1 CpG3 DNA methylation. The more stressful life events a mother had experienced in the previous 12 months (including during pregnancy), the lower her FKBP5 CpG3 methylation levels.ConclusionsFood insecurity and stressful life events during pregnancy seem to exert significant effects on maternal DNA methylation. While these stressors did not appear to impact infant DNA methylation in the present study, maternal postpartum body mass index was significantly related to infant methylation. These findings suggest that while infants may be protected from excessive maternal glucocorticoids by placental barrier activity, maternal metabolic status is still reflected in their epigenetic make-up.Trial registration This study was part of a larger matched-pair randomized controlled trial on the impact of improved on-farm crop storage on welfare, nutrition, and human health. Registration can be found in the American Economic Association (AEA) RCT Registry, RCT ID: AEARCTR-0005845.

Interaction of childhood trauma with BDNF and FKBP5 gene polymorphisms in predicting burnout in general occupational groups

Interaction of childhood trauma with BDNF and FKBP5 gene polymorphisms in predicting burnout in general occupational groups

Genetic biomarkers related to the population risks of posttraumatic stress disorder development: single nucleotide variants, gene interactions, and haplotypes

The increasing relevance of PTSD issues is associated with the escalation of military conflicts worldwide. Complex biological mechanisms also play a significant role in the pathogenesis of PTSD, including those changes observed in the hippocampus and other brain structures. Aim– to identify the most significant genetic markers predisposing the risk of PTSD manifestation, which could contribute to the development of targeted interventions focusing on the preventive measures and treatment strategies of this disorder. A literature search was conducted in the PubMed database using keywords related to the genetics of PTSD, with a publication time restriction from 2018 to 2023. Out of 623 papers, 20 articles met the inclusion criteria, describing molecular-genetic and statistical data, and the sample size of at least 60 patients with a verified PTSD diagnosis, were reviewed and analyzed in detail. The studies revealed significant associations between PTSD occurrence and single nucleotide variants (SNVs) in the FKBP5 and CRHR1 genes. Particular attention was paid to the interactions between SNVs of different genes and their association with the severity of PTSD clinical manifestations. Conclusions.Genetic markers, in particular, SNVs in the FKBP5 (rs9470080) and CRHR1 (rs1724402) genes, may play a key role as the risk factors for biological predisposition and the PTSD development. These findings would underlie the targeted interventions integrated into PTSD-related prevention measures and treatment strategies. However, further multicenter and consortium studies with unified design are required to confirm the significance of the identified associations and to specify the epigenetic aspects contributing to the PTSD manifestation and development.

The effect of single nucleotide polymorphisms on depression in combination with coronary diseases: a systematic review and meta-analysis.

Depression and coronary heart disease (CHD) have common risk mechanisms. Common single nucleotide polymorphisms (SNPs) may be associated with the risk of depression combined with coronary heart disease. This study was designed according to the PRISMA-P guidelines. We will include case-control studies and cohort studies investigating the relationship between gene SNPs and depression and coronary heart disease comorbidities. The Newcastle-Ottawa Scale (NOS) will be used to assess the risk of bias. When measuring dichotomous outcomes, we will use the odds ratio (OR) and 95% confidence interval (95%CIs) in a case-control study. Five genetic models (allele model, homozygous model, co-dominant model, dominant model, and recessive model) will be evaluated for each included study. Subgroup analysis by ethnicity will be performed. If necessary, post hoc analysis will be made according to different types. A total of 13 studies were included in this study, and the types of genes included are FKBP5 and SGK1 genes that act on glucocorticoid; miR-146a, IL-4-589, IL-6-174, TNF-α-308, CRP-717 genes that act on inflammatory mechanisms; eNOS genes from endothelial cells; HSP70 genes that act on the autoimmune response; ACE2 and MAS1 genes that act to mediate Ang(1-7) in the RAS system; 5-HTTLPR gene responsible for the transport of serotonin 5-HT and neurotrophic factor BDNF gene. There were three studies on 5-HTTLPR and BDNF genes, respectively, while there was only one study targeting FKBP5, SGK1, miR-146a, IL-4-589, IL-6-174, TNF-alpha-308, CRP-717, eNOS, HSP70, ACE2, and MAS1 genes. We did not perform a meta-analysis for genes reported in a single study, and meta-analysis was performed separately for studies exploring the 5-HTTLPR and BDNF genes. The results showed that for the 5-HTTLPR gene, there was a statistically significant association between 5-HTTLPR gene polymorphisms and depression in combination with coronary diseases (CHD-D) under the co-dominant model (LS vs LL: OR 1.76, 95%CI 1.20-2.59; SS vs LL: OR 2.80, 95%CI 1.45 to 5.41), the dominant model (LS+SS vs LL: OR 2.06, 95%CI 1.44 to 2.96), and the homozygous model (SS vs LL: OR 2.80 95%CI 1.45 to 5.5.41) were statistically significant for CHD-D, demonstrating that polymorphisms in the 5-HTTLPR gene are associated with the development of CHD-D and that the S allele in the 5-HTTLPR gene is likely to be a risk factor for CHD-D. For the BDNF gene, there were no significant differences between one of the co-dominant gene models (AA vs GG: OR 6.63, 95%CI 1.44 to 30.64), the homozygous gene model (AA vs GG: OR 6.63,95% CI 1.44 to 30.64), the dominant gene model (GA+AA vs GG: OR4.29, 95%CI 1.05 to 17.45), recessive gene model (AA vs GG+GA: OR 2.71, 95%CI 1.16 to 6.31), and allele model (A vs G: OR 2.59, 95%CI 1.18 to 5.67) were statistically significant for CHD-D, demonstrating that BDNFrs6265 gene polymorphisms are associated with the CHD-D development and that the A allele in the BDNFrs6265 gene is likely to be a risk factor for CHD-D. We analyzed the allele frequencies of SNPs reported in a single study and found that the SNPs in the microRNA146a gene rs2910164, the SNPs in the ACE2 gene rs2285666 and the SNPs in the SGK1 gene rs1743963 and rs1763509 were risk factors for the development of CHD-D. We performed a subgroup analysis of three studies involving the BDNFrs6265 gene. The results showed that European populations were more at risk of developing CHD-D than Asian populations in both dominant model (GA+AA vs GG: OR 10.47, 95%CI 3.53 to 31.08) and co-dominant model (GA vs GG: OR 6.40, 95%CI 1.98 to 20.73), with statistically significant differences. In contrast, the studies involving the 5-HTTLPR gene were all Asian populations, so subgroup analyses were not performed. We performed sensitivity analyses of studies exploring the 5-HTTLPR and BDNF rs6265 genes. The results showed that the results of the allele model, the dominant model, the recessive model, the homozygous model and the co-dominant model for both 5-HTTLPR and BDNF rs6265 genes were stable. Due to the limited number of studies of the 5-HTTLPR and BDNF genes, it was not possible to determine the symmetry of the funnel plot using Begg's funnel plot and Egger's test. Therefore, we did not assess publication bias. SNPs of the microRNA146a gene at rs2910164, the ACE2 gene at the rs2285666 and the SGK1 gene at rs1743963 and rs1763509, and the SNPs at the 5-HTTLPR and BDNF gene loci are associated with the onset of comorbid depression in coronary heart disease. We recommend that future research focus on studying SNPs' impact on comorbid depression in coronary heart disease, specifically targeting the 5-HTTLPR and BDNF gene at rs6265. https://www.crd.york.ac.uk/prospero/, identifier CRD42021229371.

The association of FKBP5 gene polymorphism with genetic susceptibility to depression and response to antidepressant treatment- a systematic review

BackgroundGiven the inconsistencies in current studies regarding the impact of FKBP5 gene polymorphisms on depression, arising from variations in study methods, subjects, and treatment strategies, this paper provides a comprehensive review of the relationship between FKBP5 gene polymorphisms and genetic susceptibility to depression, as well as their influence on response to antidepressant treatment.MethodsElectronic databases were searched up to April 11, 2023, for all literature in English and Chinese on depression, FKBP5 gene polymorphisms, and antidepressant treatment. Data extraction and quality assessment were performed for key study characteristics. Qualitative methods were used to synthesize the study results.ResultsA total of 21 studies were included, with the majority exhibiting average to moderate quality. Six SNPs (rs3800373, rs1360780, rs9470080, rs4713916, rs9296158, rs9394309) were broadly implicated in susceptibility to depression, while rs1360780 and rs3800373 were linked to antidepressant treatment sensitivity. Additionally, rs1360780 was associated with adverse reactions to antidepressant drug treatment. However, these associations were largely unconfirmed in replication studies.ConclusionsDepression is recognized as a polygenic genetic disorder, with multiple genes contributing, each exerting relatively small effects. Future studies should explore not only multiple gene interactions but also epigenetic changes. Presently, research on FKBP5 in affective disorders remains notably limited, highlighting the necessity for further investigations in this domain.

Optogenetic induction of chronic glucocorticoid exposure in early-life leads to blunted stress-response in larval zebrafish.

Early life stress (ELS) exposure alters stress susceptibility in later life and affects vulnerability to stress-related disorders, but how ELS changes the long-lasting responsiveness of the stress system is not well understood. Zebrafish provides an opportunity to study conserved mechanisms underlying the development and function of the stress response that is regulated largely by the neuroendocrine hypothalamus-pituitary-adrenal/interrenal (HPA/I) axis, with glucocorticoids (GC) as the final effector. In this study, we established a method to chronically elevate endogenous GC levels during early life in larval zebrafish. To this end, we employed an optogenetic actuator, beggiatoa photoactivated adenylyl cyclase, specifically expressed in the interrenal cells of zebrafish and demonstrate that its chronic activation leads to hypercortisolaemia and dampens the acute-stress evoked cortisol levels, across a variety of stressor modalities during early life. This blunting of stress-response was conserved in ontogeny at a later developmental stage. Furthermore, we observe a strong reduction of proopiomelanocortin (pomc)-expression in the pituitary as well as upregulation of fkbp5 gene expression. Going forward, we propose that this model can be leveraged to tease apart the mechanisms underlying developmental programming of the HPA/I axis by early-life GC exposure and its implications for vulnerability and resilience to stress in adulthood.

Identification of PPARG as key gene to link coronary atherosclerosis disease and rheumatoid arthritis via microarray data analysis.

Inflammation is the common pathogenesis of coronary atherosclerosis disease (CAD) and rheumatoid arthritis (RA). Although it is established that RA increases the risk of CAD, the underlining mechanism remained indefinite. This study seeks to explore the molecular mechanisms of RA linked CAD and identify potential target gene for early prediction of CAD in RA patients. The study utilized five raw datasets: GSE55235, GSE55457, GSE12021 for RA patients, and GSE42148 and GSE20680 for CAD patients. Gene Set Enrichment Analysis (GSEA) was used to investigate common signaling pathways associated with RA and CAD. Then, weighted gene co-expression network analysis (WGCNA) was performed on RA and CAD training datasets to identify gene modules related to single-sample GSEA (ssGSEA) scores. Overlapping module genes and differentially expressed genes (DEGs) were considered as co-susceptible genes for both diseases. Three hub genes were screened using a protein-protein interaction (PPI) network analysis via Cytoscape plug-ins. The signaling pathways, immune infiltration, and transcription factors associated with these hub genes were analyzed to explore the underlying mechanism connecting both diseases. Immunohistochemistry and qRT-PCR were conducted to validate the expression of the key candidate gene, PPARG, in macrophages of synovial tissue and arterial walls from RA and CAD patients. The study found that Fc-gamma receptor-mediated endocytosis is a common signaling pathway for both RA and CAD. A total of 25 genes were screened by WGCNA and DEGs, which are involved in inflammation-related ligand-receptor interactions, cytoskeleton, and endocytosis signaling pathways. The principal component analysis(PCA) and support vector machine (SVM) and receiver-operator characteristic (ROC) analysis demonstrate that 25 DEGs can effectively distinguish RA and CAD groups from normal groups. Three hub genes TUBB2A, FKBP5, and PPARG were further identified by the Cytoscape software. Both FKBP5 and PPARG were downregulated in synovial tissue of RA and upregulated in the peripheral blood of CAD patients and differential mRNAexpreesion between normal and disease groups in both diseases were validated by qRT-PCR.Association of PPARG with monocyte was demonstrated across both training and validation datasets in CAD. PPARG expression is observed in control synovial epithelial cells and foamy macrophages of arterial walls, but was decreased in synovial epithelium of RA patients. Its expression in foamy macrophages of atherosclerotic vascular walls exhibits a positive correlation (r = 0.6276, p = 0.0002) with CD68. Our findings suggest that PPARG may serve as a potentially predictive marker for CAD in RA patients, which provides new insights into the molecular mechanism underling RA linked CAD.

Abstract 5343: Depletion of gut microbiota with broad spectrum antibiotics drives Pten-null prostate cancer growth in mice

Abstract Gut microbes have the potential to be either promoters or inhibitors of cancer. Use of antibiotics during cancer therapy can lead to dysbiosis, which may affect treatment outcomes. Here, we examine the effects of broad-spectrum antibiotics on cancer progression in mice with Pten-null castration resistant prostate cancer (CRPC). After five or eight weeks, orchiectomized conditional Pten-null knockout (KO) mice aged 50 and 90 weeks were given two biweekly cycles of a broad-spectrum antibody cocktail (BSAbx), respectively. The effects of BSAbx on tumor burden were compared, and molecular and immunological responses were analyzed by quantitative IHC (qIHC) and qRt-PCR at week four after antibiotic treatment. BSAbx treatment resulted in tumor burdens of 1.2 and 2.4-fold higher than in control mice in mice aged 50 and 90 weeks, respectively. qIHC analysis of KI67 showed increased proliferation in stromal and cancer cells. Additionally, androgen receptor (AR) protein and gene expression levels of Ar and Ar target genes (Fkbp5, Tmprss2, and Timp4) were elevated in tumors of BSAbx-treated mice. Restoring gut microbiota by fecal microbiota transplantation (FMT) from KO mice CRPC after BSAbx restored AR transcriptional activity to basal levels and lessened tumor growth. FMT from non-castrated KO with castration-naïve prostate cancer or heathy wildtype mice further reduced AR Transcriptional activity. Moreover, altering the gut microbiota of CRPC mice with FMT from heathy mice resulted in a tendency for lower tumor burden, 21% reduction versus control mice. Immunologically, BSAbx treatment resulted in decreased CD11b+/GR1+ cells in tumors and were associated with decreased interferon-gamma (IFN-gamma), dendritic cell functions and T cell-mediated cytotoxicity gene signatures. Mice that received FMT form health mice showed enhanced T cell mediated immunity as demonstrated by higher IFN-gamma signatures and tumor abundances of CD8+ T cells expression IFN-gamma, TNF-alpha and the cytotoxic granule granzyme B. Our study shows that broad spectrum antibiotics caused dysbiosis and promoted prostate cancer growth in mice with Pten-null prostate cancer. The effects were partly mediated through the upregulation of AR signaling and the impairment of neutrophil and T cell-mediated immune responses in tumors. Citation Format: Marco A. De Velasco, Yurie Kura, Kazuko Sakai, Mitsuhisa Nishimoto, Yasunori Mori, Kazuhiro Yoshimura, Kazutoshi Fujita, Kazuto Nishio, Hirotsugu Uemura. Depletion of gut microbiota with broad spectrum antibiotics drives Pten-null prostate cancer growth in mice [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 5343.

Mother adversity and co-residence time impact mother–child similarity in genome-wide and gene-specific methylation profiles

BackgroundThe effects of adverse life events on physical and psychological health, with DNA methylation (DNAm) as a critical underlying mechanism, have been extensively studied. However, the epigenetic resemblance between mother and child in the context of neglectful caregiving, and whether it may be shaped by the emotional impact of maternal stressful events and the duration of co-residence (indexed by child age), remains unknown. The present study examined mother–child similarity in methylation profiles, considering the potential effect of mother adversity, mother empathy, neglect-control group, child age (an index of years of mother–child co-residence), and mother age. Using Illumina Epic arrays, we quantified DNAm in 115 mother–child saliva samples. We obtained a methylation similarity index by computing correlation coefficients between methylation profiles within dyads, for the entire epigenome, and five specific genes related to stress and empathy: NR3C1, FKPB5, OXTR, SCL6A4, and BDNF.ResultsThe methylation profiles of the mother–child familial pairs significantly correlated as compared to mother–child random pairs for the entire epigenome and NR3C1, FKBP5, OXTR and BDNF genes. Next, multiple linear regression models observed associations of mother adversity, child age, and neglect-control group on mother–child methylation similarity, only significant in mother–child familial pairs, after correcting for multiple comparisons. Higher mother adversity was associated with lower mother–child methylation similarity for the epigenome-wide analysis, for the BDNF gene, and in the neglect-control group for the OXTR gene. In turn, being an older child (longer co-residence) was associated with higher mother–child methylation similarity.ConclusionsMother adversity and co-residence time are modulating factors in the intergenerational methylation process that offer a window into development-dependent adaptations that can be affected by both hereditary and environmental factors, significantly observed only in biological dyads. A twofold implication for child well-being emerges, one is positive in that children of mothers exposed to life adversity or neglect did not necessarily inherit their methylation patterns. The other is concerning due to the influence of time spent living together, which affects similarity with the mother and potentially increases the risk of inheriting an epigenetic profile associated with future dysfunctional parenting patterns. This underscores the importance of the 'the earlier, the better' recommendation by the Child Protection System, which is not always followed.

Doppler ultrasonographic scan, gene expression and serum profile of immune, APPs and antioxidant markers in Egyptian buffalo–cows with clinical endometritis

The objective of this study was to elaborate Doppler ultrasonographic scan, genetic resistance and serum profile of markers associated with endometritis susceptibility in Egyptian buffalo–cows. The enrolled animals were designed as; twenty five apparently healthy buffalo–cows considered as a control group and twenty five infected buffalo with endometritis. There were significant (p < 0.05) increased of cervical diameter, endometrium thickness, uterine horn diameter, TAMEAN, TAMAX and blood flow through middle uterine artery with significant decrease of PI and RI values in endometritis buffalo–cows. Gene expression levels were considerably higher in endometritis-affected buffaloes than in resistant ones for the genes A2M, ADAMTS20, KCNT2, MAP3K4, MAPK14, FKBP5, FCAMR, TLR2, IRAK3, CCl2, EPHA4, and iNOS. The RXFP1, NDUFS5, TGF-β, SOD3, CAT, and GPX genes were expressed at substantially lower levels in endometritis-affected buffaloes. The PCR-DNA sequence verdicts of healthy and affected buffaloes revealed differences in the SNPs in the amplified DNA bases related to endometritis for the investigated genes. However, MAP3K4 elicited a monomorphic pattern. There was a significant decrease of red blood cells (RBCs) count, Hb and packed cell volume (PCV) with neutrophilia, lymphocytosis and monocytosis in endometritis group compared with healthy ones. The serum levels of Hp, SAA, Cp, IL-6, IL-10, TNF-α, NO and MDA were significantly (P˂0.05) increased, along with reduction of CAT, GPx, SOD and TAC in buffalo–cows with endometritis compared to healthy ones. The variability of Doppler ultrasonographic scan and studied genes alongside alterations in the serum profile of investigated markers could be a reference guide for limiting buffalo endometritis through selective breeding of natural resistant animals.

DNA methylation variation after a parenting program for child conduct problems: Findings from a randomized controlled trial.

This study investigated associations of the Incredible Years (IY) parenting program with children's DNA methylation. Participants were 289 Dutch children aged 3-9 years (75% European ancestry, 48% female) with above-average conduct problems. Saliva was collected 2.5 years after families were randomized to IY or care as usual (CAU). Using an intention-to-treat approach, confirmatory multiple-regression analyses revealed no significant differences between the IY and CAU groups in children's methylation levels at the NR3C1 and FKBP5 genes. However, exploratory epigenome-wide analyses revealed nine differentially methylated regions between groups, coinciding with SLAMF1, MITF, FAM200B, PSD3, SNX31, and CELSR1. The study provides preliminary evidence for associations of IY with children's salivary methylation levels and highlights the need for further research into biological outcomes of parenting programs.

Multimodal Associations of FKBP5 Methylation With Emotion-Regulatory Brain Circuits

BackgroundUnderstanding the biological processes that underlie individual differences in emotion regulation and stress responsivity is a key challenge for translational neuroscience. The gene FKBP5 is a core regulator in molecular stress signaling that is implicated in the development of psychiatric disorders. However, it remains unclear how FKBP5 DNA methylation in peripheral blood is related to individual differences in measures of neural structure and function and their relevance to daily-life stress responsivity. MethodsHere, we characterized multimodal correlates of FKBP5 DNA methylation by combining epigenetic data with neuroimaging and ambulatory assessment in a sample of 395 healthy individuals. ResultsFirst, we showed that FKBP5 demethylation as a psychiatric risk factor was related to an anxiety-associated reduction of gray matter volume in the ventromedial prefrontal cortex, a brain area that is involved in emotion regulation and mental health risk and resilience. This effect of epigenetic upregulation of FKBP5 on neuronal structure is more pronounced where FKBP5 is epigenetically downregulated at baseline. Leveraging 208 functional magnetic resonance imaging scans during a well-established emotion-processing task, we found that FKBP5 DNA methylation in peripheral blood was associated with functional differences in prefrontal-limbic circuits that modulate affective responsivity to daily stressors, which we measured using ecological momentary assessment in daily life. ConclusionsOverall, we demonstrated how FKBP5 contributes to interindividual differences in neural and real-life affect regulation via structural and functional changes in prefrontal-limbic brain circuits.

Methylation Patterns of the FKBP5 Gene in Association with Childhood Maltreatment and Depressive Disorders.

Childhood maltreatment is an important risk factor for adult depression and has been associated with changes in the hypothalamic pituitary adrenal (HPA) axis, including cortisol secretion and methylation of the FKBP5 gene. Furthermore, associations between depression and HPA changes have been reported. This study investigated the associations of whole-blood FKBP5 mRNA levels, serum cortisol levels, childhood maltreatment, and depressive symptoms with the whole-blood methylation status (assessed via target bisulfite sequencing) of 105 CpGs at the FKBP5 locus using data from the general population-based Study of Health in Pomerania (SHIP) (N = 203). Both direct and interaction effects with the rs1360780 single-nucleotide polymorphism were investigated. Nominally significant associations of main effects on methylation of a single CpG site were observed at intron 3, intron 7, and the 3'-end of the gene. Additionally, methylation at two clusters at the 3'-end and intron 7 were nominally associated with childhood maltreatment × rs1360780 and depressive symptoms × rs1360780, respectively. The results add to the understanding of molecular mechanisms underlying the emergence of depression and could aid the development of personalised depression therapy and drug development.

Study protocol for a three-arm randomized controlled trial investigating the effectiveness, cost-utility, and physiological effects of a fully self-guided digital Acceptance and Commitment Therapy for Spanish patients with fibromyalgia.

Fibromyalgia (FM) is a prevalent pain syndrome with significant healthcare and societal costs. The aim of the SMART-FM-SP study is to determine the effectiveness, cost-utility, and physiological effects in patients with FM of a digital intervention (STANZA®) currently marketed in the United States, which delivers smartphone-based, fully self-guided Acceptance and Commitment Therapy (Digital ACT) for treating FM-related symptoms. A single-site, parallel-group, superiority, randomized controlled trial (RCT) will be conducted, including a total of 360 adults diagnosed with FM. Individuals will be randomly allocated (1:1:1) to treatment as usual (TAU), to TAU plus 12 weeks of treatment with Digital ACT, or to TAU plus 12 weeks of treatment with digital symptom tracking (i.e. FibroST). Participants will be assessed at baseline, post-treatment, and 6-month follow-up. An intention-to-treat analysis using linear mixed models will be computed to analyze the effects of Digital ACT on functional impairment (primary outcome), as measured by the Fibromyalgia Impact Questionnaire Revised at 6 months from the inception of the treatment. Secondary outcomes include impression of change, symptoms of distress, pain catastrophising, quality of life, cost-utility, and selected biomarkers (cortisol and cortisone, immune-inflammatory markers, and FKBP5 gene polymorphisms). The role of ACT-related processes of change will be tested with path analyses. This study is the first RCT that tests Digital ACT for Spanish patients with FM. Results will be important not only for patients and clinicians, but also for policy makers by examining the cost-utility of the app in a public healthcare context.

Development of FKBP5 ASOs to mitigate tau pathology

AbstractBackgroundAlzheimer’s disease (AD) is a progressive neurodegenerative disorder characterized by the accumulation of abnormal protein aggregates, including tau tangles, in the brain. FKBP51 (encoded by FKBP5 gene) is a chaperone protein that regulates tau and has been implicated in AD pathology. FKBP51 overexpression in the brains of tau transgenic mice correlates with increased tau oligomers and neuronal toxicity, whereas siRNA mediated knockdown of FKBP5 decreased tau levels in cell culture models. In this study, we developed antisense oligonucleotides (ASOs) to target FKBP5, in an effort to lower tau levels. We hypothesize that ASOs targeting FKBP5 will reduce FKBP51, which will decrease tau levels and improve tau‐associated deficits.MethodWe designed and synthesized vivo‐morpholino ASOs that specifically bind to and target FKBP5 mRNA degradation. We tested three ASOs in vitro using human neuroglioma and mouse hippocampal neuronal cultures but encountered tissue toxicity when using direct injections into the brains of wild‐type mice. To overcome this, we designed and synthesized locked‐nucleic acid (LNA) GapmeR ASOs targeting regions conserved between human and mouse FKBP5. These have been tested in human neuroglioma and mouse hippocampal neuroblastoma cells lines for their ability to decrease dexamethasone induced FKBP5 upregulation and assessed for toxicity.ResultInitial screening of vivo morpholino ASOs resulted in 50% ‐ 80% reduction in dexamethasone induced FKBP51 levels at 10 µM. This was further corroborated in mouse primary cortico‐hippocampal neurons where FKBP51 levels were reduced by 50% ‐ 75%, which correlated with significant reduction in total tau levels. However, in vivo pilot studies showed tissue toxicity for our control construct. LNA GapmeR ASOs reduced FKBP51 levels at much lower concentrations (&lt;10 nM) with no apparent toxicity.Conclusion Fkbp5 ASOs have shown promising results at decreasing FKBP51 and total tau levels. Future studies will include further testing in vivo for efficacy and safety, followed by studies in tau transgenic mice.