The transcriptional regulator KLF15 is necessary for myoblast differentiation and muscle regeneration by activating FKBP5.

Successful muscle regeneration following injury is essential for functional homeostasis of skeletal muscles. Krüppel-like factor 15 (KLF15) is a metabolic transcriptional regulator in the muscles. However, little is known regarding its function in muscle regeneration. Here, we examined microarray datasets from the Gene Expression Omnibus database, which indicated downregulated KLF15 in muscles from patients with various muscle diseases. Additionally, we found that Klf15 knockout (Klf15KO) impaired muscle regeneration following injury in mice. Furthermore, KLF15 expression was robustly induced during myoblast differentiation. Myoblasts with KLF15 deficiency showed a marked reduction in their fusion capacity. Unbiased transcriptome analysis of muscles on day 7 postinjury revealed downregulated genes involved in cell differentiation and metabolic processes in Klf15KO muscles. The FK506-binding protein 51 (FKBP5), a positive regulator of myoblast differentiation, was ranked as one of the most strongly downregulated genes in the Klf15KO group. A mechanistic search revealed that KLF15 binds directly to the promoter region of FKBP5 and activates FKBP5 expression. Local delivery of FKBP5 rescued the impaired muscle regeneration in Klf15KO mice. Our findings reveal a positive regulatory role of KLF15 in myoblast differentiation and muscle regeneration by activating FKBP5 expression. KLF15 signaling may be a novel therapeutic target for muscle disorders associated with injuries or diseases.

Chronic adolescent stress alters GR-FKBP5 interactions in the hippocampus of adult female rats.

Chronic stress exposure during development can have lasting behavioral consequences that differ in males and females. More specifically, increased depressive behaviors in females, but not males, are observed in both humans and rodent models of chronic stress. Despite these known stress-induced outcomes, the molecular consequences of chronic adolescent stress in the adult brain are less clear. The stress hormone corticosterone activates the glucocorticoid receptor, and activity of the receptor is regulated through interactions with co-chaperones-such as the immunophilin FK506 binding proteins 5 (FKBP5). Previously, it has been reported that the adult stress response is modified by a history of chronic stress; therefore, the current study assessed the impact of chronic adolescent stress on the interactions of the glucocorticoid receptor (GR) with its regulatory co-chaperone FKBP5 in response to acute stress in adulthood. Although protein presence for FKBP5 did not differ by group, assessment of GR-FKBP5 interactions demonstrated that adult females with a history of chronic adolescent stress had elevated GR-FKBP5 interactions in the hippocampus following an acute stress challenge which could potentially contribute to a reduced translocation pattern given previous literature describing the impact of FKBP5 on GR activity. Interestingly, the altered co-chaperone interactions of the GR in the stressed female hippocampus were not coupled to an observable difference in transcription of GR-regulated genes. Together, these studies show that chronic adolescent stress causes lasting changes to co-chaperone interactions with the glucocorticoid receptor following stress exposure in adulthood and highlight the potential role that FKBP5 plays in these modifications. Understanding the long-term implications of adolescent stress exposure will provide a mechanistic framework to guide the development of interventions for adult disorders related to early life stress exposures.

Differential impact of prenatal PTSD symptoms and preconception trauma exposure on placental NR3C1 and FKBP5 methylation.

Perinatal stress is associated with altered placental methylation, which plays a critical role in fetal development and infant outcomes. This proof-of-concept pilot study investigated the impact of lifetime trauma exposure and perinatal PTSD symptoms on epigenetic regulation of placenta glucocorticoid signaling genes (NR3C1 and FKBP5). Lifetime trauma exposure and PTSD symptoms during pregnancy were assessed in a racially/ethnically diverse sample of pregnant women (N = 198). Participants were categorized into three groups: (1) No Trauma (-T); (2) Trauma, No Symptoms (T - S); and (3) Trauma and Symptoms (T + S). Placental tissue was analyzed via bisulfite pyrosequencing for degree of methylation at the NR3C1 promoter and FKBP5 regulatory regions. Analyses of covariance were used to test group differences in percentages of NR3C1 and FKBP5 methylation overall and at each CpG site. We found a significant impact of PTSD symptoms on placental NR3C1 methylation. Compared to the -T group, the T + S group had greater NR3C1 methylation overall and at CpG6, CpG8, CpG9, and CpG13, but lower methylation at CpG5. The T + S group had significantly higher NR3C1 methylation overall and at CpG8 compared to the T - S group. There were no differences between the T - S group and - T group. Additionally, no group differences emerged for FKBP5 methylation. Pregnant trauma survivors with PTSD symptoms exhibited differential patterns of placental NR3C1 methylation compared to trauma survivors without PTSD symptoms and pregnant women unexposed to trauma. Results highlight the critical importance of interventions to address the mental health of pregnant trauma survivors.

Manipulation of a social signal affects DNA methylation of a stress-related gene in a free-living bird.

Social status directly affects the health of humans and other animals. Low status individuals receive more antagonistic encounters, have fewer supportive relationships and have worse health outcomes. However, the physiological and cellular processes that mediate the relationship between the social environment and health are incompletely known. Epigenetic regulation of the hypothalamic-pituitary-adrenal (HPA) axis, the neuroendocrine pathway that activates in response to stressors, may be one process that is sensitive to the social environment. Here, we experimentally manipulated plumage, a key social signal in female tree swallows (Tachycineta bicolor) and quantified methylation of four genes in the HPA axis before and after treatment. We found that dulling the white breast plumage affected methylation in one gene, CRHR1; however, the effect depended on the original brightness of the bird. Methylation in this gene was correlated with baseline corticosterone levels, suggesting that DNA methylation of CRHR1 helps regulate glucocorticoid production in this species. Methylation in two other genes, FKBP5 and GR, changed over the course of the experiment, independent of treatment. These results show that methylation of these genes is labile into adulthood and suggest that epigenetic regulation of the HPA axis could help birds respond to current environmental conditions.

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

Both the BDNF gene rs6265 and the FKBP5 gene rs1360780 polymorphisms are independently associated with adult psychotic-like experiences, when exposed to high childhood abuse; however, it remains unclear whether the relationship between childhood abuse and burnout is moderated by these two single nucleotide polymorphisms (SNPs). Furthermore, there is an interaction between glucocorticoid receptor transcriptional activity and BDNF signaling. Therefore, we investigated the interaction of these two SNPs with childhood trauma in predicting burnout. We recruited 990 participants (mean age 33.06 years, S.D. = 6.31) from general occupational groups and genotyped them for rs6265 and rs1360780. Burnout, childhood trauma, resilience, and job stress were measured through a series of rating scales. Gene-by-environment and gene-by-gene-by-environment interactions were examined using linear hierarchical regression and PROCESS macro in SPSS. Covariates included demographics and resilience. We found that rs6265 moderated the association between job stress and emotional exhaustion. Both rs6265 and rs1360780 moderated the association between childhood abuse and cynicism. There was significant interaction of childhood abuse × rs6265 × rs1360780 on emotional exhaustion and reduced personal accomplishment, so that rs6265 CC genotype and rs1360780 TT genotype together predicted higher levels of emotional exhaustion under high childhood abuse, while rs6265 TT genotype and rs1360780 CC genotype together exerted a resilient effect on reduced personal accomplishment in the face of childhood abuse. Our findings suggest that the rs6265 CC genotype and rs1360780 TT genotype may jointly contribute to increased risk of burnout under childhood trauma.

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

BACKGROUND: Given 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. METHODS: Electronic 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. RESULTS: A 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. CONCLUSIONS: Depression 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.

FKBP5 deficiency attenuates calcium oxalate kidney stone formation by suppressing cell-crystal adhesion, apoptosis and macrophage M1 polarization via inhibition of NF-κB signaling.

Surgical crushing of stones alone has not addressed the increasing prevalence of kidney stones. A promising strategy is to tackle the kidney damage and crystal aggregation inherent in kidney stones with the appropriate therapeutic target. FKBP prolyl isomerase 5 (FKBP5) is a potential predictor of kidney injury, but its status in calcium oxalate (CaOx) kidney stones is not clear. This study attempted to elucidate the role and mechanism of FKBP5 in CaOx kidney stones. Lentivirus and adeno-associated virus were used to control FKBP5 expression in a CaOx kidney stone model. Transcriptomic sequencing and immunological assays were used to analyze the mechanism of FKBP5 deficiency in CaOx kidney stones. The results showed that FKBP5 deficiency reduced renal tubular epithelial cells (RTEC) apoptosis and promoted cell proliferation by downregulating BOK expression. It also attenuated cell-crystal adhesion by downregulating the expression of CDH4. In addition, it inhibited M1 polarization and chemotaxis of macrophages by suppressing CXCL10 expression in RTEC. Moreover, the above therapeutic effects were exerted by inhibiting the activation of NF-κB signaling. Finally, in vivo experiments showed that FKBP5 deficiency attenuated stone aggregation and kidney injury in mice. In conclusion, this study reveals that FKBP5 deficiency attenuates cell-crystal adhesion, reduces apoptosis, promotes cell proliferation, and inhibits macrophage M1 polarization and chemotaxis by inhibiting NF-κB signaling. This provides a potential therapeutic target for CaOx kidney stones.

Reducing FKBP51 Expression in the Ventral Hippocampus Decreases Auditory Fear Conditioning in Male Rats.

Fear conditioning evokes a physiologic release of glucocorticoids that assists learning. As a cochaperone in the glucocorticoid receptor complex, FKBP51 modulates stress-induced glucocorticoid signaling and may influence conditioned fear responses. This study combines molecular and behavioral approaches to examine whether locally reducing FKBP51 expression in the ventral hippocampus is sufficient to affect fear-related behaviors. We hypothesized that reducing FKBP51 expression in the VH would increase glucocorticoid signaling to alter auditory fear conditioning. Adult male rats were injected with an adeno-associated virus (AAV) vector expressing short hairpin - RNAs (shRNA) targeting FKBP5 into the ventral hippocampus to reduce FKBP5 levels or a control AAV. Infusion of FKBP5-shRNA into the ventral hippocampus decreased auditory fear acquisition and recall. Although animals injected with FKBP5-shRNA showed less freezing during extinction recall, the difference was due to a reduced fear recall rather than improved extinction. Reducing ventral hippocampus FKBP51 did not affect exploratory behavior in either the open field test or the elevated zero maze test but did increase passive behavior in the forced swim test, suggesting that the reduction in auditory fear recall was not due to more active responses to acute stress. Furthermore, lower ventral hippocampus FKBP51 levels did not alter corticosterone release in response to restraint stress, suggesting that the reduced fear recall was not due to lower corticosterone release. Our findings suggest FKBP51 in the ventral hippocampus plays a selective role in modulating fear-learning processes and passive behavioral responses to acute stress rather than hypothalamic-pituitary-adrenal axis reactivity or exploratory responses.

Alternative splicing of FKBP5 gene exerts control over T lymphocyte expansion.

FKBP51 is constitutively expressed by immune cells. As other FKBP family members, FKBP51 acts as a coreceptor for the natural products FK506 and rapamycin, which exhibit immunosuppressive effects. However, little is known about the intrinsic role of this large FKBP in the primary function of lymphocytes, that is, the adaptive immune response against foreign antigens, for example, pathogens. This paper aimed to investigate whether FKBP51 expression was modulated during lymphocyte activation. Moreover, as we recently identified a splicing isoform of FKBP51, namely FKBP51s, we also measured this splice protein, along with the canonical one, at different times of a peripheral blood mononuclear cell culture stimulated via T cell receptor. Our results show that the two FKBP51 isoforms were alternatively induced during the proliferative burst. Canonical FKBP51 increased in the time window between 48 and 96 h and its expression levels correlated with cyclin D levels. FKBP51s transiently increased earlier, at 24-36 h to reappearing later, at 120 h, when cyclin D expression returned at resting levels and proliferation ceased. Interestingly, within these two specific timeframes, FKBP51s accumulated in the nucleus. Here FKBP51s colocalized with the Foxp3 transcription factor at 36 h. Regulatory T cell (Treg) counts significantly decreased when FKBP51s was downmodulated. The coculture suppression assay suggested that FKBP51s supports the suppressive capability of Tregs. At 120 h, chromatin immunoprecipitation experiments found FKBP51s linked to CCND1 gene, suggesting a possible effect on gene transcription regulation, as previously demonstrated in melanoma. In conclusion, our study shows that FKBP5 isoforms are upregulated during lymphocyte activation, albeit on different timeframes. The activation of canonical FKBP51 coincides with proliferation hallmarks; FKBP5 splicing occurs early to sustain Treg development and late when proliferation ceases.

Extensive evaluation of DNA methylation of functional elements in the murine Fkbp5 locus using high-accuracy DNA methylation measurement via targeted bisulfite sequencing.

FKBP5 is an important stress-regulatory gene implicated in stress-related psychiatric diseases. Single nucleotide polymorphisms of the FKBP5 gene were shown to interact with early life stress to alter the glucocorticoid-related stress response and moderate disease risk. Demethylation of cytosine-phosphate-guanine-dinucleotides (CpGs) in regulatory glucocorticoid-responsive elements was suggested to be the mediating epigenetic mechanism for long-term stress effects, but studies on Fkbp5 DNA methylation (DNAm) in rodents are so far limited. We evaluated the applicability of high-accuracy DNA methylation measurement via targeted bisulfite sequencing (HAM-TBS), a next-generation sequencing-based technology, to allow a more in-depth characterisation of the DNA methylation of the murine Fkbp5 locus in three different tissues (blood, frontal cortex and hippocampus). In this study, we not only increased the number of evaluated sites in previously described regulatory regions (in introns 1 and 5), but also extended the evaluation to novel, possibly relevant regulatory regions of the gene (in intron 8, the transcriptional start site, the proximal enhancer and CTCF-binding sites within the 5'UTR). We here describe the assessment of HAM-TBS assays for a panel of 157 CpGs with possible functional relevance in the murine Fkbp5 gene. DNAm profiles were tissue-specific, with lesser differences between the two brain regions than between the brain and blood. Moreover, we identified DNAm changes in the Fkbp5 locus after early life stress exposure in the frontal cortex and blood. Our findings indicate that HAM-TBS is a valuable tool for broader exploration of the DNAm of the murine Fkbp5 locus and its involvement in the stress response.

Associations of psychiatric disease and ageing with FKBP5 expression converge on superficial layer neurons of the neocortex.

Identification and characterisation of novel targets for treatment is a priority in the field of psychiatry. FKBP5 is a gene with decades of evidence suggesting its pathogenic role in a subset of psychiatric patients, with potential to be leveraged as a therapeutic target for these individuals. While it is widely reported that FKBP5/FKBP51 mRNA/protein (FKBP5/1) expression is impacted by psychiatric disease state, risk genotype and age, it is not known in which cell types and sub-anatomical areas of the human brain this occurs. This knowledge is critical to propel FKBP5/1-targeted treatment development. Here, we performed an extensive, large-scale postmortem study (n = 1024) of FKBP5/1, examining neocortical areas (BA9, BA11 and ventral BA24/BA24a) derived from subjects that lived with schizophrenia, major depression or bipolar disorder. With an extensive battery of RNA (bulk RNA sequencing, single-nucleus RNA sequencing, microarray, qPCR, RNAscope) and protein (immunoblot, immunohistochemistry) analysis approaches, we thoroughly investigated the effects of disease state, ageing and genotype on cortical FKBP5/1 expression including in a cell type-specific manner. We identified consistently heightened FKBP5/1 levels in psychopathology and with age, but not genotype, with these effects strongest in schizophrenia. Using single-nucleus RNA sequencing (snRNAseq; BA9 and BA11) and targeted histology (BA9, BA24a), we established that these disease and ageing effects on FKBP5/1 expression were most pronounced in excitatory superficial layer neurons of the neocortex, and this effect appeared to be consistent in both the granular and agranular areas examined. We then found that this increase in FKBP5 levels may impact on synaptic plasticity, as FKBP5 gex levels strongly and inversely correlated with dendritic mushroom spine density and brain-derived neurotrophic factor (BDNF) levels in superficial layer neurons in BA11. These findings pinpoint a novel cellular and molecular mechanism that has potential to open a new avenue of FKBP51 drug development to treat cognitive symptoms in psychiatric disorders.

Cannabidiol alleviates neuroinflammation and attenuates neuropathic pain via targeting FKBP5.

Microglia is a heterogeneous population that mediates neuroinflammation in the central nervous system (CNS) and plays a crucial role in developing neuropathic pain. FKBP5 facilitates the assembly of the IκB kinase (IKK) complex for the activation of NF-κB, which arises as a novel target for treating neuropathic pain. In this study, cannabidiol (CBD), a main active component of Cannabis, was identified as an antagonist of FKBP5. In vitro protein intrinsic fluorescence titration showed that CBD directly bound to FKBP5. Cellular thermal shift assay (CETSA) indicated that CBD binding increased the FKBP5 stability, which implies that FKBP5 is the endogenous target of CBD. CBD was found to inhibit the assembly of the IKK complex and the activation of NF-κB, therefore blocking LPS-induced NF-κB downstream pro-inflammatory factors NO, IL-1ß, IL-6 and TNF-α. Stern-Volmer analysis and protein thermal shift assay revealed that tyrosine 113 (Y113) of FKBP5 was critical for FKBP5 interacting with CBD, which is consistent with in silico molecular docking simulation. FKBP5 Y113 mutation (Y113A) alleviated the effect of CBD inhibiting LPS-induced pro-inflammatory factors overproduction. Furthermore, systemic administration of CBD inhibited chronic constriction injury (CCI)-induced microglia activation and FKBP5 overexpression in lumbar spinal cord dorsal horn. These data imply that FKBP5 is an endogenous target of CBD.

Intracellular negative feedback mechanisms in blubber and muscle moderate acute stress responses in fasting seals.

Animals may limit the cost of stress responses during key life history stages such as breeding and molting by reducing tissue sensitivity to energy-mobilizing stress hormones (e.g. cortisol). We measured expression of genes encoding glucocorticoid receptor (GR, NR3C1), GR inhibitor (FKBP5) and cortisol-inactivating enzyme (HSD11B2) in blubber and muscle of northern elephant seals before and after stress axis stimulation by adrenocorticotropic hormone (ACTH) early and late in a fasting period associated with molting. ACTH elevated cortisol levels for >24 h and increased FKBP5 and HSD11B2 expression while downregulating NR3C1 expression in blubber and muscle, suggesting robust intracellular negative feedback in peripheral tissues. This feedback was maintained over prolonged fasting, despite differences in baseline cortisol and gene expression levels between early and late molt, suggesting that fasting-adapted animals use multiple tissue-specific, intracellular negative feedback mechanisms to modulate downstream impacts of acute stress responses during key life history stages.

LncRNA CASC19 Enhances the Radioresistance of Nasopharyngeal Carcinoma by Regulating the miR-340-3p/FKBP5 Axis.

Radioresistance remains a serious obstacle encountered in the radiotherapy of nasopharyngeal carcinoma (NPC). Both mRNAs and non-coding RNAs (ncRNAs), including long ncRNA (lncRNA) and microRNA (miRNA), play essential roles in radiosensitivity. However, the comprehensive expression profiles and competing endogenous RNA (ceRNA) regulatory networks among lncRNAs, miRNAs, and mRNAs in NPC radioresistance are still bewildering. In this study, we performed an RNA-sequencing (RNA-seq) assay in the radioresistant NPC cells CNE2R and its parental cells CNE2 to identify the differentially expressed lncRNAs, miRNAs, and mRNAs. The ceRNA networks containing lncRNAs, miRNAs, and mRNAs were predicted on the basis of the Pearson correlation coefficients and authoritative miRanda databases. In accordance with bioinformatic analysis of the data of the tandem mass tag (TMT) assay of CNE2R and CNE2 cells and the gene chip assay of radioresistant NPC samples in pre- and post-radiotherapy, the radioresistance-related signaling network of lncRNA CASC19, miR-340-3p, and FKBP5 was screened and further verified using an RT-qPCR assay. CASC19 was positively associated with FKBP5 expression while negatively correlated with miR-340-3p, and the target binding sites of CASC19/miR-340-3p and miR-340-3p/FKBP5 were confirmed using a dual-luciferase reporter assay. Moreover, using an mRFP-GFP-LC3 maker, it was found that autophagy contributed to the radioresistance of NPC. MiR-340-3p inhibition or FKBP5 overexpression could rescue the suppression of autophagy and radioresistance induced by CASC19 knockdown in CNE2R cells. In conclusion, the CASC19/miR-340-3p/FKBP5 network may be instrumental in regulating NPC radioresistance by enhancing autophagy, which provides potential new therapeutic targets for NPC.

Genetic Contributors to PTSD: the Role of SNVs, Gene Interactions and Haplotypes for Developing PTSD Prevention Measures. A Comprehensive Review.

BACKGROUND: Post-traumatic stress disorder (PTSD) is a trauma- or stressor-related mental health condition with high socioeconomic burden. We aimed in this review to identify promising genetic markers predisposing for PTSD, which might serve in the design subsequent studies aiming to develop PTSD prevention and remediation measures. SUBJECTS AND METHODS: Our search queries in the PubMed database yielded 547 articles, of which 20 met our inclusion criteria for further analysis: published between 2018 and 2022, original research, containing molecular-genetic and statistical data, containing diagnosis verification methods, PTSD as a primary condition, and a sample of at least 60 patients. RESULTS: Among the 20 analyzed studies were reports of significant associations between PTSD and: FKBP5 variants rs9470080, regardless of the C or T allele; two FKBP5 haplotypes (A-G-C-C and A-G-C-T); gene-gene DRDхANNK1-COMT (rs1800497 × rs6269) and OXTR-DRD2 (rs2268498 × rs1801028); C-allele of CRHR1 (rs1724402). Other findings, such as the association of FKBP5 haplotypes (A-G-C-C, A-G-C-T) and the FKBP5-CRHR1 genotype, were of lesser statistical significance and less extensively studied. CONCLUSIONS: Although our literature analysis implicates certain genetic factors in PTSD, our understanding of the polygenic nature underlying the disorder remains limited, especially considering the hitherto underexplored epigenetic mechanisms. Future research endeavors should prioritize exploring these aspects to provide a more nuanced understanding of PTSD and its genetic underpinnings.

A network meta-analysis of stress mediators in suicide behaviour.

Stress homeostatic mediators are the most consistently anomalous biomarkers observed in suicide and may therefore point to a common 'core biology' of stress susceptibility, and suicidal behaviour. Previously reported meta-analyses have demonstrated aberrant levels of stress cortisol and inflammatory cytokines in suicide patients compared to controls, and significant associations between the stress regulator FK506-binding protein 51 (FKBP5) gene and suicidal behaviour. Although these independent studies were investigated as separate entities in suicide, stress mediators interact in a dynamic system, collectively giving rise to system changes physiologically, and ultimately psychologically and behaviourally. It is therefore important to study the dynamic network these stress mediators. Network meta-analysis allows for the simultaneous comparison of more than two biological mediators, and for comparisons to be made between mediators that have not been directly compared before, using previously reported, pooled meta data. Such network approaches may help study the complex biological phenomena of suicide and may provide better prediction of biological risk of suicidal states. METHODS: This study aimed to establish the comparative relationships between key stress mediators in suicidal patients compared to non-suicidal controls using a random-effects network meta-analysis approach.. The key stress mediators included cortisol, six inflammatory markers (interleukin-6 (IL-6), interleukin-4 (IL-4), interleukin-2 (IL-2), tumour necrosis factor-a (TNF-α), interferon (IFN-y) and transforming growth factor ß (TGF-ß), and the FKBP5 single nucleotide polymorphism (SNP) allele. Data was derived from three previously published meta-analysis. The study population comprised of 1348 suicidal patients, defined as suicide attempters, completers, or patients with severe suicidal ideation, and 1750 non-suicidal controls, defined as healthy controls and psychiatric patients without suicidal ideation or previous attempts. RESULTS: Pair-wise indirect effects of stress mediators in suicide compared to controls demonstrated that relative to the effect of the FKBP5 risk SNP allele on suicide risk, the magnitude of differences (suicide vs control) for the levels of IL-2 (SMD -0.72; 95% CI, -0.135 to -0.09 and IL-4 (SMD -0.71; 95% CI, -1.34 to -0.08) were significantly smaller (with 95% confidence intervals not crossing the null). The comparative relationships between stress mediators in suicidal behaviour demonstrates that the dynamic stress network relationship is dysregulated in suicide patients when compared to controls. CONCLUSIONS: This model suggests that a genetic stress susceptibility with downstream abnormal cortisol stress axis functioning, together with anomalous interactions between the inflammatory system, may be one of the neurobiological correlates of suicide behaviour. This biological state may leave the individual physiologically susceptible and unable to cope with environmental stressors, which is consistent with the stress-diathesis hypothesis of suicide behaviour.

Stress-related cognitive style is related to volumetric change of the hippocampus and FK506 binding protein 5 polymorphism in post-traumatic stress disorder.

BACKGROUND: Patients with post-traumatic stress disorder (PTSD) show a different stress-related cognitive style compared with healthy controls (HC). The FK506 binding protein 5 gene (FKBP5), one of the PTSD known risk factors, is involved in the stress response through the hypothalamic-pituitary-adrenal axis and brain volumetric alterations. The present study aimed to uncover the neural correlates of stress-related cognitive styles through the analysis of the regional brain volumes and FKBP5 genotype in patients with PTSD compared with HC. METHODS: In this study, 51 patients with PTSD and 94 HC were assessed for stress-related cognitive styles, PTSD symptoms severity, and genotype of FKBP5 single nucleotide polymorphisms, and underwent T1-weighted structural magnetic resonance imaging. Diagnosis-by-genotype interaction for regional brain volumes was examined in 16 brain regions of interest. RESULTS: Patients with PTSD showed significantly higher levels of catastrophizing, ruminative response, and repression, and reduced distress aversion and positive reappraisal compared with HC (p < 0.001). Significant diagnosis-by-genotype interactions for regional brain volumes were observed for bilateral hippocampi and left frontal operculum. A significant positive correlation between the severity of the repression and left hippocampal volume was found in a subgroup of patients with PTSD with FKBP5 rs3800373 (AA genotype) or rs1360780 (CC genotype). CONCLUSIONS: The present study showed the influences of FKBP5 genotype on the distorted cognitive styles in PTSD by measuring the volumetric alteration of hippocampal regions, providing a possible role of the hippocampus and left frontal operculum as significant neurobiological correlates of PTSD.

Cadmium regulates FKBP5 through miR-9-5p and induces carp lymphocyte apoptosis.

Cadmium (Cd) is an environmental pollutant produced by industrial activities, which has no known physiological benefits to organisms. In our previous study, the transcriptomic profiles of carp head kidney exposed to Cd was analyzed by genomics technique, and confirmed that miRNAs are important in the head kidney injury of carp induced by Cd, but the specific biological mechanism was unclear. In order to further explore the effect of Cd on carp head kidney lymphocyte damage, we established a model of Cd exposure in vitro. The results showed that Cd could increase the expression of Bax (Bcl-2 associated X protein), Caspase9 (Cysteinyl aspartate specific proteinase 9) and Caspase3 (Cysteinyl aspartate specific proteinase 3), inhibit the expression of Bcl-2 (B cell lymphoma/leukemia 2), and induce apoptosis of carp head kidney lymphocytes. In our previous study, we screened the differentially expressed miRNA in Cd-treated lymphocytes by high-throughput sequencing, and found that there was a significant difference in the expression of miR-9-5p. The expression trend of miR-9-5p in the vitro model was the same as that of high-throughput sequencing. We screened the differentially expressed gene FKBP5 (FK506-binding protein 51) in lymphocytes treated with Cd. It was confirmed by double luciferase reporter gene analysis that FKBP5 was the target gene of miR-9-5p. We established the overexpression/knockdown model of miR-9-5p in carp head kidney lymphocyte in vitro. The results showed that miR-9-5p could inhibit the expression of FKBP5, increase the phosphorylation level of Akt, inhibit apoptosis and improve the cell survival rate in carp head kidney lymphocytes. Together, Cd could down-regulate the expression of miR-9-5p, target up-regulate the expression of FKBP5, inhibit the phosphorylation of Akt, and promote the apoptosis of carp head kidney lymphocytes through mitochondrial pathway.

The association of FKBP5 gene methylation, adolescents' sex, and depressive symptoms among Chinese adolescents: a nested case-control study.

BACKGROUND: Depressive symptoms among adolescents are a serious health concern around the world. Altered DNA methylation in the FK506 binding protein 5 (FKBP5) gene has been reported to regulate stress response, which has been reported to be closely associated with depressive symptoms. However, most of the contributing studies have been conducted among adults and relatively few studies have considered the effect of disparate social influences and sex differences on the DNA methylation of FKBP5 in persons with depressive symptoms. The present study aimed to test the associations of FKBP5 DNA methylation and depressive symptoms among adolescents and explore possible sex differences in the foregoing associations. METHODS: This study was conducted using a nested case-control design within a longitudinal cohort study from January 2019 to December 2019. Adolescents aged 12 to 17 years from 69 classes in 10 public high schools located in Guangdong province of China participated in this research. Students with persistent depressive symptoms that reported having depressive symptoms at both baseline and follow-up were treated as the case group, and those without depressive symptoms were randomly selected as the control group. Our study finally included 87 cases and 151 controls. Quantitative methylation analyses of the selected gene were carried out by MassARRAY platform System. RESULTS: The overall DNA methylation trend of FKBP5 CpG sites in the case group was lower in comparison to the control group. Compared to healthy controls, lower methylation percentage of FKBP5-12 CpG 1 was observed in adolescents with persistent depressive symptoms after adjusting for covariates (case: 0.94 ± 2.00, control: 0.47 ± 0.92; F = 5.41, P = 0.021), although the statistical significance of the difference was lost after false discovery rate correction (q > 0.05). In addition, the hypomethylation of FKBP5-12 CpG 1 was approaching significance after adjustment for social-environmental factors (aOR = 0.77; P = 0.055), which indicated that no independent association was detected between hypomethylation of FKBP5 CpG sites and persistent depressive symptoms. Furthermore, in the present study, we were unable to identify sex differences in the association of FKBP5 gene methylation with depressive symptoms. CONCLUSION: The decreased methylation level of FKBP5 was observed in adolescents with persistent depressive symptoms, albeit non-significant after correction for multiple testing. Our results presented here are preliminary and underscore the complex gene-environment interactions relevant to the risk for depressive symptoms.

Childhood adversity predicts black young adults' DNA methylation-based accelerated aging: A dual pathway model.

We expand upon prior work (Gibbons et al., ) relating childhood stressor effects, particularly harsh childhood environments, to risky behavior and ultimately physical health by adding longer-term outcomes - deoxyribonucleic acid (DNA) methylation-based measures of accelerated aging (DNAm-aging). Further, following work on the effects of early exposure to danger (McLaughlin et al., ), we also identify an additional pathway from harsh childhood environments to DNAm-aging that we label the danger/FKBP5 pathway, which includes early exposure to dangerous community conditions that are thought to impact glucocorticoid regulation and pro-inflammatory mechanisms. Because different DNAm-aging indices provide different windows on accelerated aging, we contrast effects on early indices of DNAm-aging based on chronological age with later indices that focused on predicting biological outcomes. We utilize data from Family and Community Health Study participants (N = 449) from age 10 to 29. We find that harshness influences parenting, which, in turn, influences accelerated DNAm-aging through the risky cognitions and substance use (i.e., behavioral) pathway outlined by Gibbons et al. (). Harshness is also associated with increased exposure to threat/danger, which, in turn, leads to accelerated DNAm-aging through effects on FKBP5 activity and enhanced pro-inflammatory tendencies (i.e., the danger/FKBP5 pathway).