H2A.Z chaperones converge on E2F target genes for melanoma cell proliferation.

High levels of H2A.Z promote melanoma cell proliferation and correlate with poor prognosis. However, the role of the two distinct H2A.Z histone chaperone complexes SRCAP and P400-TIP60 in melanoma remains unclear. Here, we show that individual subunit depletion of SRCAP, P400, and VPS72 (YL1) results in not only the loss of H2A.Z deposition into chromatin but also a reduction of H4 acetylation in melanoma cells. This loss of H4 acetylation is particularly found at the promoters of cell cycle genes directly bound by H2A.Z and its chaperones, suggesting a coordinated regulation between H2A.Z deposition and H4 acetylation to promote their expression. Knockdown of each of the three subunits downregulates E2F1 and its targets, resulting in a cell cycle arrest akin to H2A.Z depletion. However, unlike H2A.Z deficiency, loss of the shared H2A.Z chaperone subunit YL1 induces apoptosis. Furthermore, YL1 is overexpressed in melanoma tissues, and its upregulation is associated with poor patient outcome. Together, these findings provide a rationale for future targeting of H2A.Z chaperones as an epigenetic strategy for melanoma treatment.

Wdr5 mediates self-renewal and reprogramming via the embryonic stem cell core transcriptional network.

The embryonic stem (ES) cell transcriptional and chromatin-modifying networks are critical for self-renewal maintenance. However, it remains unclear whether these networks functionally interact and, if so, what factors mediate such interactions. Here, we show that WD repeat domain 5 (Wdr5), a core member of the mammalian Trithorax (trxG) complex, positively correlates with the undifferentiated state and is a regulator of ES cell self-renewal. We demonstrate that Wdr5, an "effector" of H3K4 methylation, interacts with the pluripotency transcription factor Oct4. Genome-wide protein localization and transcriptome analyses demonstrate overlapping gene regulatory functions between Oct4 and Wdr5. The Oct4-Sox2-Nanog circuitry and trxG cooperate in activating transcription of key self-renewal regulators, and furthermore, Wdr5 expression is required for the efficient formation of induced pluripotent stem (iPS) cells. We propose an integrated model of transcriptional and epigenetic control, mediated by select trxG members, for the maintenance of ES cell self-renewal and somatic cell reprogramming.

Histone variant macroH2A1 regulates synchronous firing of replication origins in the inactive X chromosome.

MacroH2A has been linked to transcriptional silencing, cell identity, and is a hallmark of the inactive X chromosome (Xi). However, it remains unclear whether macroH2A plays a role in DNA replication. Using knockdown/knockout cells for each macroH2A isoform, we show that macroH2A-containing nucleosomes slow down replication progression rate in the Xi reflecting the higher nucleosome stability. Moreover, macroH2A1, but not macroH2A2, regulates the number of nano replication foci in the Xi, and macroH2A1 downregulation increases DNA loop sizes corresponding to replicons. This relates to macroH2A1 regulating replicative helicase loading during G1 by interacting with it. We mapped this interaction to a phenylalanine in macroH2A1 that is not conserved in macroH2A2 and the C-terminus of Mcm3 helicase subunit. We propose that macroH2A1 enhances the licensing of pre-replication complexes via DNA helicase interaction and loading onto the Xi.

Harnessing BET Inhibitor Sensitivity Reveals AMIGO2 as a Melanoma Survival Gene.

Bromodomain and extraterminal domain inhibitors (BETi) represent promising therapeutic agents for metastatic melanoma, yet their mechanism of action remains unclear. Here we interrogated the transcriptional effects of BETi and identified AMIGO2, a transmembrane molecule, as a BET target gene essential for melanoma cell survival. AMIGO2 is upregulated in melanoma cells and tissues compared to human melanocytes and nevi, and AMIGO2 silencing in melanoma cells induces G1/S arrest followed by apoptosis. We identified the pseudokinase PTK7 as an AMIGO2 interactor whose function is regulated by AMIGO2. Epigenomic profiling and genome editing revealed that AMIGO2 is regulated by a melanoma-specific BRD2/4-bound promoter and super-enhancer configuration. Upon BETi treatment, BETs are evicted from these regulatory elements, resulting in AMIGO2 silencing and changes in PTK7 proteolytic processing. Collectively, this study uncovers mechanisms underlying the therapeutic effects of BETi in melanoma and reveals the AMIGO2-PTK7 axis as a targetable pathway for metastatic melanoma.

Predictors of pharmacotherapy outcomes for body dysmorphic disorder: a machine learning approach.

BACKGROUND: Serotonin-reuptake inhibitors (SRIs) are first-line pharmacotherapy for the treatment of body dysmorphic disorder (BDD), a common and severe disorder. However, prior research has not focused on or identified definitive predictors of SRI treatment outcomes. Leveraging precision medicine techniques such as machine learning can facilitate the prediction of treatment outcomes. METHODS: The study used 10-fold cross-validation support vector machine (SVM) learning models to predict three treatment outcomes (i.e. response, partial remission, and full remission) for 97 patients with BDD receiving up to 14-weeks of open-label treatment with the SRI escitalopram. SVM models used baseline clinical and demographic variables as predictors. Feature importance analyses complemented traditional SVM modeling to identify which variables most successfully predicted treatment response. RESULTS: SVM models indicated acceptable classification performance for predicting treatment response with an area under the curve (AUC) of 0.77 (sensitivity = 0.77 and specificity = 0.63), partial remission with an AUC of 0.75 (sensitivity = 0.67 and specificity = 0.73), and full remission with an AUC of 0.79 (sensitivity = 0.70 and specificity = 0.79). Feature importance analyses supported constructs such as better quality of life and less severe depression, general psychopathology symptoms, and hopelessness as more predictive of better treatment outcome; demographic variables were least predictive. CONCLUSIONS: The current study is the first to demonstrate that machine learning algorithms can successfully predict treatment outcomes for pharmacotherapy for BDD. Consistent with precision medicine initiatives in psychiatry, the current study provides a foundation for personalized pharmacotherapy strategies for patients with BDD.

Mechanisms of cognitive-behavioral therapy effects on symptoms of body dysmorphic disorder: a network intervention analysis.

BACKGROUND: Body dysmorphic disorder (BDD) is a severe and undertreated condition. Although cognitive-behavioral therapy (CBT) is the first-line psychosocial treatment for this common disorder, how the intervention works is insufficiently understood. Specific pathways have been hypothesized, but only one small study has examined the precise nature of treatment effects of CBT, and no prior study has examined the effects of supportive psychotherapy (SPT). METHODS: This study re-examined a large trial (n = 120) comparing CBT to SPT for BDD. Network intervention analyses were used to explore symptom-level data across time. We computed mixed graphical models at multiple time points to examine relative differences in direct and indirect effects of the two interventions. RESULTS: In the resulting networks, CBT and SPT appeared to differentially target certain symptoms. The largest differences included CBT increasing efforts to disengage from and restructure unhelpful thoughts and resist BDD rituals, while SPT was directly related to improvement in BDD-related insight. Additionally, the time course of differences aligned with the intended targets of CBT; cognitive effects emerged first and behavioral effects second, paralleling cognitive restructuring in earlier sessions and the emphasis on exposure and ritual prevention in later sessions. Differences in favor of CBT were most consistent for behavioral targets. CONCLUSIONS: CBT and SPT primarily affected different symptoms. To improve patient care, the field needs a better understanding of how and when BDD treatments and treatment components succeed. Considering patient experiences at the symptom level and over time can aid in refining or reorganizing treatments to better fit patient needs.

Histone Variant H2A.Z.2 Mediates Proliferation and Drug Sensitivity of Malignant Melanoma.

Histone variants are emerging as key regulatory molecules in cancer. We report a unique role for the H2A.Z isoform H2A.Z.2 as a driver of malignant melanoma. H2A.Z.2 is highly expressed in metastatic melanoma, correlates with decreased patient survival, and is required for cellular proliferation. Our integrated genomic analyses reveal that H2A.Z.2 controls the transcriptional output of E2F target genes in melanoma cells. These genes are highly expressed and display a distinct signature of H2A.Z occupancy. We identify BRD2 as an H2A.Z-interacting protein, levels of which are also elevated in melanoma. We further demonstrate that H2A.Z.2-regulated genes are bound by BRD2 and E2F1 in an H2A.Z.2-dependent manner. Importantly, H2A.Z.2 deficiency sensitizes melanoma cells to chemotherapy and targeted therapies. Collectively, our findings implicate H2A.Z.2 as a mediator of cell proliferation and drug sensitivity in malignant melanoma, holding translational potential for novel therapeutic strategies.

Efficacy of App-Based Cognitive Behavioral Therapy for Body Dysmorphic Disorder with Coach Support: Initial Randomized Controlled Clinical Trial.

INTRODUCTION: Body dysmorphic disorder (BDD) is severe, chronic, and undertreated. Apps could substantially improve treatment access. OBJECTIVE: We provide an initial test of the usability and efficacy of coach-supported app-based cognitive behavioral therapy (CBT) for BDD. The Perspectives app covers core treatment components: psychoeducation, cognitive restructuring, exposure with response prevention, mindfulness, attention retraining, and relapse prevention. METHODS: A randomized waitlist-controlled trial was conducted. Adults (N = 80) with primary BDD were assigned to 12 weeks of Perspectives or waitlist. Coaches promoted engagement and answered questions via in-app messaging and phone calls. BDD severity was measured at baseline, mid-treatment, and end of treatment by blinded independent evaluators (Yale-Brown Obsessive Compulsive Scale Modified for BDD; BDD-YBOCS). Secondary outcomes included BDD-related insight, depression, quality of life, and functioning. RESULTS: App uptake and satisfaction were high. In intent-to-treat analyses, Perspectives app-based CBT was associated with significantly lower BDD-YBOCS severity at end of treatment (M [SD]: 16.8 [7.5]) compared to the waitlist (26.7 [6.2]; p < 0.001, d = 1.44). App-based CBT was associated with greater improvements across all secondary measures, with medium to large effects. CONCLUSIONS: Perspectives, supported by a bachelor's-level coach, is an efficacious, scalable treatment for adults with BDD.

Human Support in App-Based Cognitive Behavioral Therapies for Emotional Disorders: Scoping Review.

BACKGROUND: Smartphone app-based therapies offer clear promise for reducing the gap in available mental health care for people at risk for or people with mental illness. To this end, as smartphone ownership has become widespread, app-based therapies have become increasingly common. However, the research on app-based therapies is lagging behind. In particular, although experts suggest that human support may be critical for increasing engagement and effectiveness, we have little systematic knowledge about the role that human support plays in app-based therapy. It is critical to address these open questions to optimally design and scale these interventions. OBJECTIVE: The purpose of this study is to provide a scoping review of the use of human support or coaching in app-based cognitive behavioral therapy for emotional disorders, identify critical knowledge gaps, and offer recommendations for future research. Cognitive behavioral therapy is the most well-researched treatment for a wide range of concerns and is understood to be particularly well suited to digital implementations, given its structured, skill-based approach. METHODS: We conducted systematic searches of 3 databases (PubMed, PsycINFO, and Embase). Broadly, eligible articles described a cognitive behavioral intervention delivered via smartphone app whose primary target was an emotional disorder or problem and included some level of human involvement or support (coaching). All records were reviewed by 2 authors. Information regarding the qualifications and training of coaches, stated purpose and content of the coaching, method and frequency of communication with users, and relationship between coaching and outcomes was recorded. RESULTS: Of the 2940 titles returned by the searches, 64 (2.18%) were eligible for inclusion. This review found significant heterogeneity across all of the dimensions of coaching considered as well as considerable missing information in the published articles. Moreover, few studies had qualitatively or quantitatively evaluated how the level of coaching impacts treatment engagement or outcomes. Although users tend to self-report that coaching improves their engagement and outcomes, there is limited and mixed supporting quantitative evidence at present. CONCLUSIONS: Digital mental health is a young but rapidly expanding field with great potential to improve the reach of evidence-based care. Researchers across the reviewed articles offered numerous approaches to encouraging and guiding users. However, with the relative infancy of these treatment approaches, this review found that the field has yet to develop standards or consensus for implementing coaching protocols, let alone those for measuring and reporting on the impact. We conclude that coaching remains a significant hole in the growing digital mental health literature and lay out recommendations for future data collection, reporting, experimentation, and analysis.

Multivalent binding of PWWP2A to H2A.Z regulates mitosis and neural crest differentiation.

Replacement of canonical histones with specialized histone variants promotes altering of chromatin structure and function. The essential histone variant H2A.Z affects various DNA-based processes via poorly understood mechanisms. Here, we determine the comprehensive interactome of H2A.Z and identify PWWP2A as a novel H2A.Z-nucleosome binder. PWWP2A is a functionally uncharacterized, vertebrate-specific protein that binds very tightly to chromatin through a concerted multivalent binding mode. Two internal protein regions mediate H2A.Z-specificity and nucleosome interaction, whereas the PWWP domain exhibits direct DNA binding. Genome-wide mapping reveals that PWWP2A binds selectively to H2A.Z-containing nucleosomes with strong preference for promoters of highly transcribed genes. In human cells, its depletion affects gene expression and impairs proliferation via a mitotic delay. While PWWP2A does not influence H2A.Z occupancy, the C-terminal tail of H2A.Z is one important mediator to recruit PWWP2A to chromatin. Knockdown of PWWP2A in Xenopus results in severe cranial facial defects, arising from neural crest cell differentiation and migration problems. Thus, PWWP2A is a novel H2A.Z-specific multivalent chromatin binder providing a surprising link between H2A.Z, chromosome segregation, and organ development.

PTEN interacts with the transcription machinery on chromatin and regulates RNA polymerase II-mediated transcription.

Regulation of RNA polymerase II (RNAPII)-mediated transcription controls cellular phenotypes such as cancer. Phosphatase and tensin homologue deleted on chromosome ten (PTEN), one of the most commonly altered tumor suppressors in cancer, affects transcription via its role in antagonizing the PI3K/AKT signaling pathway. Using co-immunoprecipitations and proximal ligation assays we provide evidence that PTEN interacts with AFF4, RNAPII, CDK9, cyclin T1, XPB and CDK7. Using ChIP-seq, we show that PTEN co-localizes with RNAPII and binds to chromatin in promoter and putative enhancer regions identified by histone modifications. Furthermore, we show that loss of PTEN affects RNAPII occupancy in gene bodies and further correlates with gene expression changes. Interestingly, PTEN binds to promoters and negatively regulates the expression of genes involved in transcription including AFF4 and POL2RA, which encodes a subunit of RNAPII. Loss of PTEN also increased cells' sensitivity to transcription inhibition via small molecules, which could provide a strategy to target PTEN-deficient cancers. Overall, our work describes a previously unappreciated role of nuclear PTEN, which by interacting with the transcription machinery in the context of chromatin exerts an additional layer of regulatory control on RNAPII-mediated transcription.

Treatment for Anxiety and Comorbid Depressive Disorders: Transdiagnostic Cognitive-Behavioral Strategies.

Anxiety and depressive disorders are common psychiatric conditions with high rates of co-occurrence. Although traditional cognitive-behavioral therapy (CBT) protocols targeting individual anxiety and depressive disorder diagnoses have been shown to be effective, such "single-diagnosis" approaches pose challenges for providers who treat patients with multiple comorbidities and for large-scale dissemination of and training in evidence-based psychological treatments. To help meet this need, newer "transdiagnostic" CBT interventions targeting shared underlying features across anxiety, depressive, and related disorders have been developed in recent years. Here we provide a rationale for and description of the transdiagnostic CBT model, followed by an overview of key therapeutic strategies included in transdiagnostic CBT protocols for patients with anxiety disorders and comorbid depression. We conclude with a brief review of the empirical evidence in support of transdiagnostic CBT for individuals with anxiety and depressive disorders and identify directions for future research.

ATRX-mediated chromatin association of histone variant macroH2A1 regulates α-globin expression.

The histone variant macroH2A generally associates with transcriptionally inert chromatin; however, the factors that regulate its chromatin incorporation remain elusive. Here, we identify the SWI/SNF helicase ATRX (α-thalassemia/MR, X-linked) as a novel macroH2A-interacting protein. Unlike its role in assisting H3.3 chromatin deposition, ATRX acts as a negative regulator of macroH2A's chromatin association. In human erythroleukemic cells deficient for ATRX, macroH2A accumulates at the HBA gene cluster on the subtelomere of chromosome 16, coinciding with the loss of α-globin expression. Collectively, our results implicate deregulation of macroH2A's distribution as a contributing factor to the α-thalassemia phenotype of ATRX syndrome.

Unique and predictive relationships between components of cognitive vulnerability and symptoms of depression.

BACKGROUND: Cognitive vulnerability theories of depression outline multiple, distinct inferential biases constitutive of cognitive vulnerability to depression. These include attributing negative events to internal, stable, and global factors, assuming that negative events will lead to further negative consequences, and inferring that negative events reflect negative characteristics about the self. Extant research has insufficiently examined these biases as distinct, limiting our understanding of how the individual cognitive vulnerability components interrelate and confer risk for depression symptoms. Thus, we conducted exploratory network analyses to examine the relationships among the five components of negative cognitive style and explore how components may differentially relate to depressive symptoms in adolescents. METHODS: Participants completed measures of negative cognitive style twice over a two-year period. We estimated Graphical Gaussian Models using contemporaneous data and computed a cross-lagged panel network using temporal data from baseline and 2-year follow-up. RESULTS: Results reveal interesting structural dynamics among facets of negative cognitive style and depressive symptoms. For example, results point to biases towards stable and future-oriented inferences as highly influential among negative cognitive style components. The temporal model revealed the internal attributions component to be heavily influenced by depressive symptoms among adolescents, whereas stable and global attributions most influenced future symptoms. CONCLUSIONS: This study presents novel approaches for investigating cognitive style and depression. From this perspective, perhaps more precise predictions can be made about how cognitive risk factors will lead to the development or worsening of psychopathology.

Less is more? Effects of exhaustive vs. minimal emotion labelling on emotion regulation strategy planning.

Previous research suggests that labelling emotions, or describing affective states using emotion words, facilitates emotion regulation. But how much labelling promotes emotion regulation? And which emotion regulation strategies does emotion labelling promote? Drawing on cognitive theories of emotion, we predicted that labelling emotions using fewer words would be less confusing and would facilitate forms of emotion regulation requiring more cognitively demanding processing of context. Participants (N = 82) mentally immersed themselves in an emotional vignette, were randomly assigned to an exhaustive or minimal emotion labelling manipulation, and then completed an emotion regulation strategy planning task. Minimal (vs. exhaustive) emotion labelling promoted higher subjective emotional clarity. Furthermore, in terms of specific emotion regulation strategies, minimal emotion labelling prompted more plans for problem solving and marginally more plans for reappraisal, but did not affect plans for behavioural activation or social support seeking. We discuss implications for the cognitive mechanisms supporting the generation of emotion regulation strategies.

Acute aerobic exercise helps overcome emotion regulation deficits.

Although colloquial wisdom and some studies suggest an association between regular aerobic exercise and emotional well-being, the nature of this link remains poorly understood. We hypothesised that aerobic exercise may change the way people respond to their emotions. Specifically, we tested whether individuals experiencing difficulties with emotion regulation would benefit from a previous session of exercise and show swifter recovery than their counterparts who did not exercise. Participants (N = 80) completed measures of emotion response tendencies, mood, and anxiety, and were randomly assigned to either stretch or jog for 30 minutes. All participants then underwent the same negative and positive mood inductions, and reported their emotional responses. Analyses showed that more perceived difficulty generating regulatory strategies and engaging in goal-directed behaviours after the negative mood induction predicted more intense and persistent negative affect in response to the stressor, as would be expected. Interactions revealed that aerobic exercise attenuated these effects. Moderate aerobic exercise may help attenuate negative emotions for participants initially experiencing regulatory difficulties. This study contributes to the literature on aerobic exercise's therapeutic effects with experimental data, specifically in the realm of emotional processing.

The histone variant macroH2A suppresses melanoma progression through regulation of CDK8.

Cancer is a disease consisting of both genetic and epigenetic changes. Although increasing evidence demonstrates that tumour progression entails chromatin-mediated changes such as DNA methylation, the role of histone variants in cancer initiation and progression currently remains unclear. Histone variants replace conventional histones within the nucleosome and confer unique biological functions to chromatin. Here we report that the histone variant macroH2A (mH2A) suppresses tumour progression of malignant melanoma. Loss of mH2A isoforms, histone variants generally associated with condensed chromatin and fine-tuning of developmental gene expression programs, is positively correlated with increasing malignant phenotype of melanoma cells in culture and human tissue samples. Knockdown of mH2A isoforms in melanoma cells of low malignancy results in significantly increased proliferation and migration in vitro and growth and metastasis in vivo. Restored expression of mH2A isoforms rescues these malignant phenotypes in vitro and in vivo. We demonstrate that the tumour-promoting function of mH2A loss is mediated, at least in part, through direct transcriptional upregulation of CDK8. Suppression of CDK8, a colorectal cancer oncogene, inhibits proliferation of melanoma cells, and knockdown of CDK8 in cells depleted of mH2A suppresses the proliferative advantage induced by mH2A loss. Moreover, a significant inverse correlation between mH2A and CDK8 expression levels exists in melanoma patient samples. Taken together, our results demonstrate that mH2A is a critical component of chromatin that suppresses the development of malignant melanoma, a highly intractable cutaneous neoplasm.

Medical burden in bipolar disorder: findings from the Clinical and Health Outcomes Initiative in Comparative Effectiveness for Bipolar Disorder study (Bipolar CHOICE).

OBJECTIVES: Individuals with bipolar disorder have high rates of other medical comorbidity, which is associated with higher mortality rates and worse course of illness. The present study examined common predictors of medical comorbidity. METHODS: The Clinical and Health Outcomes Initiative in Comparative Effectiveness for Bipolar Disorder study (Bipolar CHOICE) enrolled 482 participants with bipolar I or bipolar II disorder in a six-month, randomized comparative effectiveness trial. Baseline assessments included current and lifetime DSM-IV-TR diagnoses, demographic information, psychiatric and medical history, severity of psychiatric symptoms, level of functioning, and a fasting blood draw. Medical comorbidities were categorized into two groups: cardiometabolic (e.g., diabetes, hyperlipidemia, and metabolic syndrome) and non-cardiovascular (e.g., seizures, asthma, and cancer). Additionally, we looked at comorbid substance use (e.g., smoking and drug dependence). RESULTS: We found that 96.3% of participants had at least one other medical comorbidity. Older age predicted a greater likelihood of having a cardiometabolic condition. Early age of onset of bipolar symptoms was associated with a lower chance of having a cardiometabolic condition, but a greater chance of having other types of medical comorbidity. Additional predictors of other medical comorbidities in bipolar disorder included more time spent depressed, less time spent manic/hypomanic, and longer duration of illness. Medications associated with weight gain were associated with low high-density lipoprotein and abnormal triglycerides. CONCLUSIONS: There appears to be a substantial medical burden associated with bipolar disorder, highlighting the need for collaborative care among psychiatric and general medical providers to address both psychiatric and other medical needs concomitantly in this group of patients.

Histone variants: emerging players in cancer biology.

Histone variants are key players in shaping chromatin structure, and, thus, in regulating fundamental cellular processes such as chromosome segregation and gene expression. Emerging evidence points towards a role for histone variants in contributing to tumor progression, and, recently, the first cancer-associated mutation in a histone variant-encoding gene was reported. In addition, genetic alterations of the histone chaperones that specifically regulate chromatin incorporation of histone variants are rapidly being uncovered in numerous cancers. Collectively, these findings implicate histone variants as potential drivers of cancer initiation and/or progression, and, therefore, targeting histone deposition or the chromatin remodeling machinery may be of therapeutic value. Here, we review the mammalian histone variants of the H2A and H3 families in their respective cellular functions, and their involvement in tumor biology.