Sustained inactivation of the Polycomb PRC1 complex induces DNA repair defects and genomic instability in epigenetic tumors.

Cancer initiation and progression are typically associated with the accumulation of driver mutations and genomic instability. However, recent studies demonstrated that cancer can also be driven purely by epigenetic alterations, without driver mutations. Specifically, a 24-h transient downregulation of polyhomeotic (ph-KD), a core component of the Polycomb complex PRC1, is sufficient to induce epigenetically initiated cancers (EICs) in Drosophila, which are proficient in DNA repair and characterized by a stable genome. Whether genomic instability eventually occurs when PRC1 downregulation is performed for extended periods of time remains unclear. Here, we show that prolonged depletion of PH, which mimics cancer initiating events, results in broad dysregulation of DNA replication and repair genes, along with the accumulation of DNA breaks, defective repair, and widespread genomic instability in the cancer tissue. A broad misregulation of H2AK118 ubiquitylation and to a lesser extent of H3K27 trimethylation also occurs and might contribute to these phenotypes. Together, this study supports a model where DNA repair and replication defects accumulate during the tumorigenic transformation epigenetically induced by PRC1 loss, resulting in genomic instability and cancer progression.

Are language-cognition interactions bigger than a breadbox? Integrative modeling and design space thinking temper simplistic questions about causally dense phenomena.

We affirm the utility of integrative modeling, according to which it is advantageous to move beyond "one-at-a-time binary paradigms" through studies that position themselves within realistic multidimensional design spaces. We extend the integrative modeling approach to a target domain with which we are familiar, the consequences of bilingualism on mind and brain, often referred to as the "bilingual advantage." In doing so, we highlight work from our group consistent with integrative modeling.

Trithorax group proteins: switching genes on and keeping them active.

Cellular memory is provided by two counteracting groups of chromatin proteins termed Trithorax group (TrxG) and Polycomb group (PcG) proteins. TrxG proteins activate transcription and are perhaps best known because of the involvement of the TrxG protein MLL in leukaemia. However, in terms of molecular analysis, they have lived in the shadow of their more famous counterparts, the PcG proteins. Recent advances have improved our understanding of TrxG protein function and demonstrated that the heterogeneous group of TrxG proteins is of critical importance in the epigenetic regulation of the cell cycle, senescence, DNA damage and stem cell biology.

Gonadal transcriptomes associated with sex phenotypes provide potential male and female candidate genes of sex determination or early differentiation in Crassostrea gigas, a sequential hermaphrodite mollusc.

BACKGROUND: In the animal kingdom, mollusca is an important phylum of the Lophotrochozoa. However, few studies have investigated the molecular cascade of sex determination/early gonadal differentiation within this phylum. The oyster Crassostrea gigas is a sequential irregular hermaphrodite mollusc of economic, physiological and phylogenetic importance. Although some studies identified genes of its sex-determining/-differentiating pathway, this particular topic remains to be further deepened, in particular with regard to the expression patterns. Indeed, these patterns need to cover the entire period of sex lability and have to be associated to future sex phenotypes, usually impossible to establish in this sequential hermaphrodite. This is why we performed a gonadal RNA-Seq analysis of diploid male and female oysters that have not changed sex for 4 years, sampled during the entire time-window of sex determination/early sex differentiation (stages 0 and 3 of the gametogenetic cycle). This individual long-term monitoring gave us the opportunity to explain the molecular expression patterns in the light of the most statistically likely future sex of each oyster. RESULTS: The differential gene expression analysis of gonadal transcriptomes revealed that 9723 genes were differentially expressed between gametogenetic stages, and 141 between sexes (98 and 43 genes highly expressed in females and males, respectively). Eighty-four genes were both stage- and sex-specific, 57 of them being highly expressed at the time of sex determination/early sex differentiation. These 4 novel genes including Trophoblast glycoprotein-like, Protein PML-like, Protein singed-like and PREDICTED: paramyosin, while being supported by RT-qPCR, displayed sexually dimorphic gene expression patterns. CONCLUSIONS: This gonadal transcriptome analysis, the first one associated with sex phenotypes in C. gigas, revealed 57 genes highly expressed in stage 0 or 3 of gametogenesis and which could be linked to the future sex of the individuals. While further study will be needed to suggest a role for these factors, some could certainly be original potential actors involved in sex determination/early sex differentiation, like paramyosin and could be used to predict the future sex of oysters.

HOX genes promote cell proliferation and are potential therapeutic targets in adrenocortical tumours.

BACKGROUND: Understanding the pathways that drive adrenocortical carcinoma (ACC) is essential to the development of more effective therapies. This study investigates the role of the transcription factor HOXB9 and other HOX factors in ACC and its treatment. METHODS: We used transgenic mouse models to determine the role of Hoxb9 in adrenal tumour development. Patient transcriptomic data was analysed for the expression of HOX genes and their association with disease. Drug response studies on various adrenocortical models were done to establish novel therapeutic options. RESULTS: Our human ACC dataset analyses showed high expression of HOXB9, and other HOX factors, are associated with poorer prognosis. Transgenic overexpression of Hoxb9 in the adrenal cortex of mice with activated Ctnnb1 led to larger adrenal tumours. This phenotype was preferentially observed in male mice and was characterised by more proliferating cells and an increase in the expression of cell cycle genes, including Ccne1. Adrenal tumour cells were found to be dependent on HOX function for survival and were sensitive to a specific peptide inhibitor. CONCLUSIONS: These studies show Hoxb9 can promote adrenal tumour progression in a sex-dependent manner and have identified HOX factors as potential drug targets, leading to novel therapeutic approaches in ACC.

Cell Fate and Developmental Regulation Dynamics by Polycomb Proteins and 3D Genome Architecture.

Targeted transitions in chromatin states at thousands of genes are essential drivers of eukaryotic development. Therefore, understanding the in vivo dynamics of epigenetic regulators is crucial for deciphering the mechanisms underpinning cell fate decisions. This review illustrates how, in addition to its cell memory function, the Polycomb group of transcriptional regulators orchestrates temporal, cell and tissue-specific expression of master genes during development. These highly sophisticated developmental transitions are dependent on the context- and tissue-specific assembly of the different types of Polycomb Group (PcG) complexes, which regulates their targeting and/or activities on chromatin. Here, an overview is provided of how PcG complexes function at multiple scales to regulate transcription, local chromatin environment, and higher order structures that support normal differentiation and are perturbed in tumorigenesis.

Steroidogenic differentiation and PKA signaling are programmed by histone methyltransferase EZH2 in the adrenal cortex.

Adrenal cortex steroids are essential for body homeostasis, and adrenal insufficiency is a life-threatening condition. Adrenal endocrine activity is maintained through recruitment of subcapsular progenitor cells that follow a unidirectional differentiation path from zona glomerulosa to zona fasciculata (zF). Here, we show that this unidirectionality is ensured by the histone methyltransferase EZH2. Indeed, we demonstrate that EZH2 maintains adrenal steroidogenic cell differentiation by preventing expression of GATA4 and WT1 that cause abnormal dedifferentiation to a progenitor-like state in Ezh2 KO adrenals. EZH2 further ensures normal cortical differentiation by programming cells for optimal response to adrenocorticotrophic hormone (ACTH)/PKA signaling. This is achieved by repression of phosphodiesterases PDE1B, 3A, and 7A and of PRKAR1B. Consequently, EZH2 ablation results in blunted zF differentiation and primary glucocorticoid insufficiency. These data demonstrate an all-encompassing role for EZH2 in programming steroidogenic cells for optimal response to differentiation signals and in maintaining their differentiated state.

Having Therapeutic Conversations With Fathers Grieving the Death of a Child.

A child's death is a traumatic life experience for parents. Health-care professionals (HCPs) have sought guidance on how to intervene with grieving parents, particularly with fathers. Having therapeutic conversations is an effective way for HCPs to support grieving fathers. In our previous study, fathers identified core beliefs that influenced their experience of grief and coping. In this article, the Illness Beliefs Model was integrated with the findings to provide a framework for interventions to create open conversations, ease fathers' suffering, and thereby help their spouse and family suffering as well. This article will guide HCPs to engage in therapeutic conversations to support bereaved fathers.

Hormonal and spatial control of SUMOylation in the human and mouse adrenal cortex.

SUMOylation is a highly conserved and dynamic post-translational mechanism primarily affecting nuclear programs for adapting organisms to stressful challenges. Alteration of SUMOylation cycles leads to severe developmental and homeostatic defects and malignancy, but signals coordinating SUMOylation are still unidentified. The adrenal cortex is a zonated endocrine gland that controls body homeostasis and stress response. Here, we show that in human and in mouse adrenals, SUMOylation follows a decreasing centripetal gradient that mirrors cortical differentiation flow and delimits highly and weakly SUMOylated steroidogenic compartments, overlapping glomerulosa, and fasciculata zones. Activation of PKA signaling by acute hormonal treatment, mouse genetic engineering, or in Carney complex results in repression of small ubiquitin-like modifier (SUMO) conjugation in the inner cortex by coordinating expression of SUMO pathway inducers and repressors. Conversely, genetic activation of canonical wingless-related integration site signaling maintains high SUMOylation potential in the outer neoplastic cortex. Thus, SUMOylation is tightly regulated by signaling pathways that orchestrate adrenal zonation and diseases.-Dumontet, T., Sahut-Barnola, I., Dufour, D., Lefrançois-Martinez, A.-M., Berthon, A., Montanier, N., Ragazzon, B., Djari, C., Pointud, J.-C., Roucher-Boulez, F., Batisse-Lignier, M., Tauveron, I., Bertherat, J., Val, P., Martinez, A. Hormonal and spatial control of SUMOylation in the human and mouse adrenal cortex.

Role of Polycomb Complexes in Normal and Malignant Plasma Cells.

Plasma cells (PC) are the main effectors of adaptive immunity, responsible for producing antibodies to defend the body against pathogens. They are the result of a complex highly regulated cell differentiation process, taking place in several anatomical locations and involving unique genetic events. Pathologically, PC can undergo tumorigenesis and cause a group of diseases known as plasma cell dyscrasias, including multiple myeloma (MM). MM is a severe disease with poor prognosis that is characterized by the accumulation of malignant PC within the bone marrow, as well as high clinical and molecular heterogeneity. MM patients frequently develop resistance to treatment, leading to relapse. Polycomb group (PcG) proteins are epigenetic regulators involved in cell fate and carcinogenesis. The emerging roles of PcG in PC differentiation and myelomagenesis position them as potential therapeutic targets in MM. Here, we focus on the roles of PcG proteins in normal and malignant plasma cells, as well as their therapeutic implications.

EZH2 cooperates with E2F1 to stimulate expression of genes involved in adrenocortical carcinoma aggressiveness.

BACKGROUND: EZH2 is overexpressed and associated with poor prognosis in adrenocortical carcinoma (ACC) and its inhibition reduces growth and aggressiveness of ACC cells in culture. Although EZH2 was identified as the methyltransferase that deposits the repressive H3K27me3 histone mark, it can cooperate with transcription factors to stimulate gene transcription. METHODS: We used bioinformatics approaches on gene expression data from three cohorts of patients and a mouse model of EZH2 ablation, to identify targets and mode of action of EZH2 in ACC. This was followed by ChIP and functional assays to evaluate contribution of identified targets to ACC pathogenesis. RESULTS: We show that EZH2 mostly works as a transcriptional inducer in ACC, through cooperation with the transcription factor E2F1 and identify three positive targets involved in cell cycle regulation and mitosis i.e., RRM2, PTTG1 and ASE1/PRC1. Overexpression of these genes is associated with poor prognosis, suggesting a potential role in acquisition of aggressive ACC features. Pharmacological and siRNA-mediated inhibition of RRM2 blocks cell proliferation, induces apoptosis and inhibits cell migration, suggesting that it may be an interesting target in ACC. CONCLUSIONS: Altogether, these data show an unexpected role of EZH2 and E2F1 in stimulating expression of genes associated with ACC aggressiveness.

EZH2 is overexpressed in adrenocortical carcinoma and is associated with disease progression.

Adrenal Cortex Carcinoma (ACC) is an aggressive tumour with poor prognosis. Common alterations in patients include constitutive WNT/ß-catenin signalling and overexpression of the growth factor IGF2. However, the combination of both alterations in transgenic mice is not sufficient to trigger malignant tumour progression, suggesting that other alterations are required to allow development of carcinomas. Here, we have conducted a study of publicly available gene expression data from three cohorts of ACC patients to identify relevant alterations. Our data show that the histone methyltransferase EZH2 is overexpressed in ACC in the three cohorts. This overexpression is the result of deregulated P53/RB/E2F pathway activity and is associated with increased proliferation and poorer prognosis in patients. Inhibition of EZH2 by RNA interference or pharmacological treatment with DZNep inhibits cellular growth, wound healing and clonogenic growth and induces apoptosis of H295R cells in culture. Further growth inhibition is obtained when DZNep is combined with mitotane, the gold-standard treatment for ACC. Altogether, these observations suggest that overexpression of EZH2 is associated with aggressive progression and may constitute an interesting therapeutic target in the context of ACC.

Task difficulty modulates brain-behavior correlations in language production and cognitive control: Behavioral and fMRI evidence from a phonological go/no-go picture-naming paradigm.

Language production and cognitive control are complex processes that involve distinct yet interacting brain networks. However, the extent to which these processes interact and their neural bases have not been thoroughly examined. Here, we investigated the neural and behavioral bases of language production and cognitive control via a phonological go/no-go picture-naming task. Naming difficulty and cognitive control demands (i.e., conflict monitoring and response inhibition) were manipulated by varying the proportion of naming trials (go trials) and inhibition trials (no-go trials) across task runs. The results demonstrated that as task demands increased, participants' behavioral performance declined (i.e., longer reaction times on naming trials, more commission errors on inhibition trials) whereas brain activation generally increased. Increased activation was found not only within the language network but also in domain-general control regions. Additionally, right superior and inferior frontal and left supramarginal gyri were sensitive to increased task difficulty during both language production and response inhibition. We also found both positive and negative brain-behavior correlations. Most notably, increased activation in sensorimotor regions, such as precentral and postcentral gyri, was associated with better behavioral performance, in both successful picture naming and successful inhibition. Moreover, comparing the strength of correlations across conditions indicated that the brain-behavior correlations in sensorimotor regions that were associated with improved performance became stronger as task demands increased. Overall, our results suggest that cognitive control demands affect language production, and that successfully coping with increases in task difficulty relies on both language-specific and domain-general cognitive control regions.

mTOR pathway is activated by PKA in adrenocortical cells and participates in vivo to apoptosis resistance in primary pigmented nodular adrenocortical disease (PPNAD).

Primary pigmented nodular adrenocortical disease (PPNAD) is associated with inactivating mutations of the PRKAR1A tumor suppressor gene that encodes the regulatory subunit R1α of the cAMP-dependent protein kinase (PKA). In human and mouse adrenocortical cells, these mutations lead to increased PKA activity, which results in increased resistance to apoptosis that contributes to the tumorigenic process. We used in vitro and in vivo models to investigate the possibility of a crosstalk between PKA and mammalian target of rapamycin (mTOR) pathways in adrenocortical cells and its possible involvement in apoptosis resistance. Impact of PKA signaling on activation of the mTOR pathway and apoptosis was measured in a mouse model of PPNAD (AdKO mice), in human and mouse adrenocortical cell lines in response to pharmacological inhibitors and in PPNAD tissues by immunohistochemistry. AdKO mice showed increased mTOR complex 1 (mTORC1) pathway activity. Inhibition of mTORC1 by rapamycin restored sensitivity of adrenocortical cells to apoptosis in AdKO but not in wild-type mice. In both cell lines and mouse adrenals, rapid phosphorylation of mTORC1 targets including BAD proapoptotic protein was observed in response to PKA activation. Accordingly, BAD hyperphosphorylation, which inhibits its proapoptotic activity, was increased in both AdKO mouse adrenals and human PPNAD tissues. In conclusion, mTORC1 pathway is activated by PKA signaling in human and mouse adrenocortical cells, leading to increased cell survival, which is correlated with BAD hyperphosphorylation. These alterations could be causative of tumor formation.

WNT/ß-catenin signalling is activated in aldosterone-producing adenomas and controls aldosterone production.

Primary aldosteronism (PA) is the main cause of secondary hypertension, resulting from adrenal aldosterone-producing adenomas (APA) or bilateral hyperplasia. Here, we show that constitutive activation of WNT/ß-catenin signalling is the most frequent molecular alteration found in 70% of APA. We provide evidence that decreased expression of the WNT inhibitor SFRP2 may be contributing to deregulated WNT signalling and APA development in patients. This is supported by the demonstration that mice with genetic ablation of Sfrp2 have increased aldosterone production and ectopic differentiation of zona glomerulosa cells. We further show that ß-catenin plays an essential role in the control of basal and Angiotensin II-induced aldosterone secretion, by activating AT1R, CYP21 and CYP11B2 transcription. This relies on both LEF/TCF-dependent activation of AT1R and CYP21 regulatory regions and indirect activation of CYP21 and CYP11B2 promoters, through increased expression of the nuclear receptors NURR1 and NUR77. Altogether, these data show that aberrant WNT/ß-catenin activation is associated with APA development and suggest that WNT pathway may be a good therapeutic target in PA.

[Describing undergraduate nurses' student vision of spirituality as well as their perception of the nurse's role in this dimension] / Description des conceptions de la spiritualité et des perceptions du rôle de l'infirmière chez les étudiantes en sciences infirmières quant à la prise en compte de la dimension spirituelle du patient.

In North American society people have diverse cultural and religious affiliations. The nursing profession underlines the importance of including patients' spirituality in giving holistic care. However, studies suggest that the majority of nurses do not include the spiritual dimension on a regular basis. Therefore, we thought it important to focus on undergraduate nurses' understanding of spirituality as well as on their perception of the nurse's role in this area. We conducted a quantitative and descriptive cross-sectional study, which gave us an overall view of the students' perceptions. Three hundred and forty-five students answered an online survey which included French translations of the Spirituality and Spiritual Care Rating Scale and the Students Survey of Spiritual Care. Analysis of the results indicated that the students' perception of spirituality is a contemporary one. The majority agree that nurses should include spirituality in their care but do not feel equipped to do so adequately. A comparative analysis showed that the students' answers differed significantly depending on their cultural affiliation as well as on their affiliation or not with a religion. Recommendations for teaching purposes will also be presented.

Integrating the Illness Beliefs Model in clinical practice: a Family Systems Nursing knowledge utilization model.

To promote the integration of Family Systems Nursing (FSN) in clinical practice, we need to better understand how nurses overcome the challenges of FSN knowledge utilization. A qualitative exploratory study was conducted with 32 practicing female nurses from hospital and community settings who had received FSN intervention training and skill development based on the Illness Beliefs Model and the Calgary Family Assessment and Intervention Models. The participants were interviewed about how they utilized FSN knowledge in their nursing practice. From the data analysis, a FSN Knowledge Utilization Model emerged that involves three major components: (a) nurses' beliefs in FSN and in their FSN skills, (b) nurses' knowledge utilization strategies to address the challenges of FSN practice, and (c) FSN positive outcomes. The FSN Knowledge Utilization Model describes a circular, incremental, and iterative process used by nurses to integrate FSN in daily nursing practice. Findings point to a need for re-evaluation of educational and management strategies in clinical settings for advancing the practice of FSN.

Cg-SoxE and Cg-ß-catenin, two new potential actors of the sex-determining pathway in a hermaphrodite lophotrochozoan, the Pacific oyster Crassostrea gigas.

Sex determination is poorly known in mollusks, lophotrochozoa and most hermaphrodites. In the oyster Crassostrea gigas, an irregular successive hermaphrodite, sex determination may occur at the end of a gametogenetic cycle to prepare the next cycle. To investigate further into these aspects we have focused on orthologs of SoxE and ß-catenin, key players of the male and female gonadic differentiation respectively in mammals. Based on phylogenetic analyses, Cg-SoxE, the oyster's SoxE ortholog, is closely related to vertebrate SoxE genes while Cg-ß-catenin, the oyster's ß-catenin ortholog, is classified amongst lophotrochozoa. The mRNA expression measured by qPCR in the gonadic area during a gametogenetic cycle is maximal for Cg-SoxE when sex is indiscernible and for Cg-ß-catenin in mature females. Both expressions are localized from early germ cells to spermatocytes and pre-vitellogenic oocytes, and potentially in somatic cells. Cg-ß-catenin is also expressed in vitellogenic oocytes. These actors may be involved in early oyster gonadic differentiation, which includes sex determination. Our results enhance the understanding of sex determination in C. gigas and in mollusks and they provide additional knowledge in compared genomics of reproduction and in molecular phylogeny.

Sustained inactivation of the Polycomb PRC1 complex induces DNA repair defects and genomic instability in epigenetic tumors.

Cancer initiation and progression are typically associated with the accumulation of driver mutations and genomic instability. However, recent studies demonstrated that cancers can also be purely initiated by epigenetic alterations, without driver mutations. Specifically, a 24-hours transient down-regulation of polyhomeotic (ph-KD), a core component of the Polycomb complex PRC1, is sufficient to drive epigenetically initiated cancers (EICs) in Drosophila, which are proficient in DNA repair and are characterized by a stable genome. Whether genomic instability eventually occurs when PRC1 down-regulation is performed for extended periods of time remains unclear. Here we show that prolonged depletion of a PRC1 component, which mimics cancer initiating events, results in broad dysregulation of DNA replication and repair genes, along with the accumulation of DNA breaks, defective repair, and widespread genomic instability in the cancer tissue. A broad mis-regulation of H2AK118 ubiquitylation and to a lesser extent of H3K27 trimethylation also occurs, and might contribute to these phenotypes. Together, this study supports a model where DNA repair and replication defects amplify the tumorigenic transformation epigenetically induced by PRC1 loss, resulting in genomic instability and cancer progression.

Language diversity across home and work contexts differentially impacts age- and menopause-related declines in cognitive control in healthy females.

Menopause is associated with declines in cognitive control. However, there is individual variability in the slope of this decline. Recent work suggests that indices of cognitive control are mediated by communicative demands of the language environment. However, little is known about how the impact of bilingual experience generalizes across the lifespan, particularly in females who exhibit steeper cognitive decline due to increasing age and menopausal transition. Thus, we investigated whether diversity of language use in distinct communicative contexts modulated the effects of aging and menopause on cognitive control in an adult lifespan sample of healthy females. We performed robust linear regressions on a sample of 120 females (age range 20-65 years) to characterize age- (n = 120) and menopause-related (n = 59) declines in cognitive control (as assessed by the Wisconsin Card Sorting Test) and to determine whether they are modulated by different facets of bilingual language experience, including the diversity of language use (i.e., language entropy) in home and workplace environments. Workplace but not home language diversity modulated age- and menopause-related declines in cognitive control, suggesting that females may compensate for decline by virtue of adapting to the externally imposed demands of the language environment. These findings have implications for identifying which aspects of bilingual experience may contribute to cognitive reserve in healthy aging. (PsycInfo Database Record (c) 2024 APA, all rights reserved).