Genome-wide transcriptome profiling and development of age prediction models in the human brain.

Aging-related transcriptome changes in various regions of the healthy human brain have been explored in previous works, however, a study to develop prediction models for age based on the expression levels of specific panels of transcripts is lacking. Moreover, studies that have assessed sexually dimorphic gene activities in the aging brain have reported discrepant results, suggesting that additional studies would be advantageous. The prefrontal cortex (PFC) region was previously shown to have a particularly large number of significant transcriptome alterations during healthy aging in a study that compared different regions in the human brain. We harmonized neuropathologically normal PFC transcriptome datasets obtained from the Gene Expression Omnibus (GEO) repository, ranging in age from 21 to 105 years, and found a large number of differentially regulated transcripts in the old and elderly, compared to young samples overall, and compared female and male-specific expression alterations. We assessed the genes that were associated with age by employing ontology, pathway, and network analyses. Furthermore, we applied various established (least absolute shrinkage and selection operator (Lasso) and Elastic Net (EN)) and recent (eXtreme Gradient Boosting (XGBoost) and Light Gradient Boosting Machine (LightGBM)) machine learning algorithms to develop accurate prediction models for chronological age and validated them. Studies to further validate these models in other large populations and molecular studies to elucidate the potential mechanisms by which the transcripts identified may be related to aging phenotypes would be advantageous.

Change in screen time and overuse, and their association with psychological well-being among US-wide school-age children during the COVID-19 pandemic: analysis of the National Survey of Children's Health (NSCH) years 2018-21.

BACKGROUND: Previous studies on screen use and children's mental health during the Coronavirus Disease 2019 (COVID-19) pandemic focused only on the timeframe during the pandemic, on children between narrow age ranges, only among a subset of children who have previously reported COVID-related severe family economic hardship or worries, or did not distinguish between instructive versus recreational device usage. Thus, in this study, we analyzed trends, specifically related to recreational screen use, and associations with psychological well-being (PWB) in the years before versus during the COVID-19 pandemic, among a wide range of school-aged children, widely across the nation. METHODS: Using the National Survey of Children's Health (NSCH) years 2018-21, we analyzed a large random sample of school-aged children (6-17 years old) across the US (n = 88,823). We developed PWB issue scores (PWBIS) using self-reported measures relevant to this age group, and constructed regression models to assess the magnitude of the contribution of the pandemic on recreational screen use and PWB. RESULTS: The prevalence of recreational screen overuse and PWBIS increased significantly during the pandemic, compared to prior years. We also detected a notable effect of the pandemic on increased PWBIS, as well as its interaction term finding that it strengthened the association between screen time and PWBIS (p < 0.01 across all regression models). CONCLUSIONS: Accordingly, our results demonstrate the importance of the pandemic itself as an independent adverse factor and effect measure modifier for screen overuse and PWB more generally among all school-age children widely across the US. Our study used the most current data available, and future studies to evaluate whether these effects are persistent in the years after the pandemic are important.

A PREVENTIVE TOOL FOR PREDICTING BLOODSTREAM INFECTIONS IN CHILDREN WITH BURNS.

ABSTRACT: Introduction: Despite significant advances in pediatric burn care, bloodstream infections (BSIs) remain a compelling challenge during recovery. A personalized medicine approach for accurate prediction of BSIs before they occur would contribute to prevention efforts and improve patient outcomes. Methods: We analyzed the blood transcriptome of severely burned (total burn surface area [TBSA] ≥20%) patients in the multicenter Inflammation and Host Response to Injury ("Glue Grant") cohort. Our study included 82 pediatric (aged <16 years) patients, with blood samples at least 3 days before the observed BSI episode. We applied the least absolute shrinkage and selection operator (LASSO) machine-learning algorithm to select a panel of biomarkers predictive of BSI outcome. Results: We developed a panel of 10 probe sets corresponding to six annotated genes ( ARG2 [ arginase 2 ], CPT1A [ carnitine palmitoyltransferase 1A ], FYB [ FYN binding protein ], ITCH [ itchy E3 ubiquitin protein ligase ], MACF1 [ microtubule actin crosslinking factor 1 ], and SSH2 [ slingshot protein phosphatase 2 ]), two uncharacterized ( LOC101928635 , LOC101929599 ), and two unannotated regions. Our multibiomarker panel model yielded highly accurate prediction (area under the receiver operating characteristic curve, 0.938; 95% confidence interval [CI], 0.881-0.981) compared with models with TBSA (0.708; 95% CI, 0.588-0.824) or TBSA and inhalation injury status (0.792; 95% CI, 0.676-0.892). A model combining the multibiomarker panel with TBSA and inhalation injury status further improved prediction (0.978; 95% CI, 0.941-1.000). Conclusions: The multibiomarker panel model yielded a highly accurate prediction of BSIs before their onset. Knowing patients' risk profile early will guide clinicians to take rapid preventive measures for limiting infections, promote antibiotic stewardship that may aid in alleviating the current antibiotic resistance crisis, shorten hospital length of stay and burden on health care resources, reduce health care costs, and significantly improve patients' outcomes. In addition, the biomarkers' identity and molecular functions may contribute to developing novel preventive interventions.

Multi-Biomarker Prediction Models for Multiple Infection Episodes Following Blunt Trauma.

Severe trauma predisposes patients to multiple independent infection episodes (MIIEs), leading to augmented morbidity and mortality. We developed a method to identify increased MIIE risk before clinical signs appear, which is fundamentally different from existing approaches entailing infections' detection after their establishment. Applying machine learning algorithms to genome-wide transcriptome data from 128 adult blunt trauma patients' (42 MIIE cases and 85 non-cases) leukocytes collected ≤48 hr of injury and ≥3 days before any infection, we constructed a 15-transcript and a 26-transcript multi-biomarker panel model with the least absolute shrinkage and selection operator (LASSO) and Elastic Net, respectively, which accurately predicted MIIE (Area Under Receiver Operating Characteristics Curve [AUROC] [95% confidence intervals, CI]: 0.90 [0.84-0.96] and 0.92 [0.86-0.96]) and significantly outperformed clinical models. Gene Ontology and network analyses found various pathways to be relevant. External validation found our model to be generalizable. Our unique precision medicine approach can be applied to a wide range of patient populations and outcomes.

Denver and Marshall scores successfully predict susceptibility to multiple independent infections in trauma patients.

Trauma patients are at risk of repeated hospital-acquired infections, however predictive scores aiming to identify susceptibility to such infections are lacking. The objective of this study was to investigate whether commonly employed disease-severity scores can successfully predict susceptibility to multiple independent infectious episodes (MIIEs) among trauma patients. A secondary analysis of data derived from the prospective, longitudinal study "Inflammation and the Host Response to Injury" ("Glue Grant") was performed. 1,665 trauma patients, older than 16, were included. Patients who died within seven days from the time of injury were excluded. Five commonly used disease-severity scores [Denver, Marshall, Acute Physiology and Chronic Health Evaluation II (APACHE II), Injury Severity Score (ISS), and New Injury Severity Score (NISS)] were examined as independent predictors of susceptibility to MIIEs. The latter was defined as two or more independent infectious episodes during the index hospital stay. Multivariable logistic regression was used for the statistical analysis. 22.58% of the population was found to be susceptible to MIIEs. Denver and Marshall scores were highly predictive of the MIIE status. For every 1-unit increase in the Denver or the Marshall score, there was a respective 15% (Odds Ratio:1.15; 95% CI: 1.07-1.24; p < 0.001) or 16% (Odds Ratio:1.16; 95% CI: 1.09-1.24; p < 0.001) increase in the odds of MIIE occurrence. APACHE II, ISS, and NISS were not independent predictors of susceptibility to MIIEs. In conclusion, the Denver and Marshall scores can reliably predict which trauma patients are prone to MIIEs, prior to any clinical sign of infection. Early identification of these individuals would potentially allow the implementation of rapid, personalized, preventative measures, thus improving patient outcomes and reducing healthcare costs.

Intestinal alkaline phosphatase targets the gut barrier to prevent aging.

Gut barrier dysfunction and gut-derived chronic inflammation play crucial roles in human aging. The gut brush border enzyme intestinal alkaline phosphatase (IAP) functions to inhibit inflammatory mediators and also appears to be an important positive regulator of gut barrier function and microbial homeostasis. We hypothesized that this enzyme could play a critical role in regulating the aging process. We tested the role of several IAP functions for prevention of age-dependent alterations in intestinal homeostasis by employing different loss-of-function and supplementation approaches. In mice, there is an age-related increase in gut permeability that is accompanied by increases in gut-derived portal venous and systemic inflammation. All these phenotypes were significantly more pronounced in IAP-deficient animals. Oral IAP supplementation significantly decreased age-related gut permeability and gut-derived systemic inflammation, resulted in less frailty, and extended lifespan. Furthermore, IAP supplementation was associated with preserving the homeostasis of gut microbiota during aging. These effects of IAP were also evident in a second model system, Drosophilae melanogaster. IAP appears to preserve intestinal homeostasis in aging by targeting crucial intestinal alterations, including gut barrier dysfunction, dysbiosis, and endotoxemia. Oral IAP supplementation may represent a novel therapy to counteract the chronic inflammatory state leading to frailty and age-related diseases in humans.

Aging mechanisms-A perspective mostly from Drosophila.

A mechanistic understanding of the natural aging process, which is distinct from aging-related disease mechanisms, is essential for developing interventions to extend lifespan or healthspan. Here, we discuss current trends in aging research and address conceptual and experimental challenges in the field. We examine various molecular markers implicated in aging with an emphasis on the role of heterochromatin and epigenetic changes. Studies in model organisms have been advantageous in elucidating conserved genetic and epigenetic mechanisms and assessing interventions that affect aging. We highlight the use of Drosophila, which allows controlled studies for evaluating genetic and environmental contributors to aging conveniently. Finally, we propose the use of novel methodologies and future strategies using Drosophila in aging research.

Associations between clinical characteristics and the development of multiple organ failure after severe burns in adult patients.

To determine the association between potential risk factors and multiple organ failure (MOF) in severe burn adult patients, we performed a secondary analysis of data from the "Inflammation and the Host Response to Injury" database, which included patients from six burn centers in the United States between 2003 and 2009. Three hundred twenty-two adult patients (aged ≥16 years) with severe burns (≥20.0% total body surface area [TBSA]) were included. MOF was defined according to the Denver score. Potential risk factors were analyzed for their association with MOF. Models were built using multivariable logistic regression analysis. Eighty-eight patients (27.3%) developed MOF during the study period. We found that TBSA, age, and inhalation injury were significant risk factors for MOF. This predictive model showed good performance, with the total area under the receiver operating characteristic curve being 0.823. Moreover, among patients who developed MOF, inhalation injury was significantly associated with the development of MOF in the acute phase (within three days of injury) (adjusted odds ratio 3.1; 95% confidence interval 1.1-8.3). TBSA, age, lactate, and Denver score within 24h were associated with the late phase development of MOF. Thus, we have identified key risk factors for the onset of MOF after severe burn injury. Our findings contribute to the understanding of individualized treatment and will potentially allow for efficient allocation of resources and a lower threshold for admission to an intensive care unit, which can prevent the development of MOF and eventually reduce mortality.

Genome-wide Kdm4 histone demethylase transcriptional regulation in Drosophila.

The histone lysine demethylase 4 (Kdm4/Jmjd2/Jhdm3) family is highly conserved across species and reverses di- and tri-methylation of histone H3 lysine 9 (H3K9) and lysine 36 (H3K36) at the N-terminal tail of the core histone H3 in various metazoan species including Drosophila, C.elegans, zebrafish, mice and humans. Previous studies have shown that the Kdm4 family plays a wide variety of important biological roles in different species, including development, oncogenesis and longevity by regulating transcription, DNA damage response and apoptosis. Only two functional Kdm4 family members have been identified in Drosophila, compared to five in mammals, thus providing a simple model system. Drosophila Kdm4 loss-of-function mutants do not survive past the early 2nd instar larvae stage and display a molting defect phenotype associated with deregulated ecdysone hormone receptor signaling. To further characterize and identify additional targets of Kdm4, we employed a genome-wide approach to investigate transcriptome alterations in Kdm4 mutants versus wild-type during early development. We found evidence of increased deregulated transcripts, presumably associated with a progressive accumulation of H3K9 and H3K36 methylation through development. Gene ontology analyses found significant enrichment of terms related to the ecdysteroid hormone signaling pathway important in development, as expected, and additionally previously unidentified potential targets that warrant further investigation. Since Kdm4 is highly conserved across species, our results may be applicable more widely to other organisms and our genome-wide dataset may serve as a useful resource for further studies.

Canonical and non-canonical JAK/STAT transcriptional targets may be involved in distinct and overlapping cellular processes.

BACKGROUND: The Janus kinase-signal transducer and activator of transcription (JAK/STAT) pathway has been well-characterized as a crucial signal transduction cascade that regulates vital biological responses including development, immunity and oncogenesis. Additionally to its canonical pathway that uses the phosphorylated form of the STAT transcription factor, recently the non-canonical pathway involving heterochromatin formation by unphosphorylated STAT was recently uncovered. Considering the significant role of the JAK/STAT pathway, we used the simple Drosophila system in which the non-canonical pathway was initially characterized, to compare putative canonical versus non-canonical transcriptional targets across the genome. We analyzed microarray expression patterns of wildtype, Jak gain- and loss-of-function mutants, as well as the Stat loss-of-function mutant during embryogenesis, since the contribution of the canonical signal transduction pathway has been well-characterized in these contexts. Previous studies have also demonstrated that Jak gain-of-function and Stat mutants counter heterochromatin silencing to de-repress target genes by the non-canonical pathway. RESULTS: Compared to canonical target genomic loci, non-canonical targets were significantly more associated with sites enriched with heterochromatin-related factors (p = 0.004). Furthermore, putative canonical and non-canonical transcriptional targets identified displayed some differences in biological pathways they regulate, as determined by Gene Ontology (GO) enrichment analyses. Canonical targets were enriched mainly with genes relevant to development and immunity, as expected, whereas the non-canonical target gene set mainly showed enrichment of genes for various metabolic responses and stress response, highlighting the possibility that some differences may exist between the two loci. CONCLUSIONS: Canonical and non-canonical JAK/STAT genes may regulate distinct and overlapping sets of genes and may perform specific overall functions in physiology. Further studies at different developmental stages, or using distinct tissues may identify additional targets and provide insight into which gene targets are unique to the canonical or non-canonical pathway.

NF-κBp50 and HDAC1 Interaction Is Implicated in the Host Tolerance to Infection Mediated by the Bacterial Quorum Sensing Signal 2-Aminoacetophenone.

Some bacterial quorum sensing (QS) small molecules are important mediators of inter-kingdom signaling and impact host immunity. The QS regulated small volatile molecule 2-aminoacetophenone (2-AA), which has been proposed as a biomarker of Pseudomonas aeruginosa colonization in chronically infected human tissues, is critically involved in "host tolerance training" that involves a distinct molecular mechanism of host chromatin regulation through histone deacetylase (HDAC)1. 2-AA's epigenetic reprogramming action enables host tolerance to high bacterial burden and permits long-term presence of P. aeruginosa without compromising host survival. Here, to further elucidate the molecular mechanisms of 2-AA-mediated host tolerance/resilience we investigated the connection between histone acetylation status and nuclear factor (NF)-κB signaling components that together coordinate 2-AA-mediated control of transcriptional activity. We found increased NF-κBp65 acetylation levels in 2-AA stimulated cells that are preceded by association of CBP/p300 and increased histone acetyltransferase activity. In contrast, in 2-AA-tolerized cells the protein-protein interaction between p65 and CBP/p300 is disrupted and conversely, the interaction between p50 and co-repressor HDAC1 is enhanced, leading to repression of the pro-inflammatory response. These results highlight how a bacterial QS signaling molecule can establish a link between intracellular signaling and epigenetic reprogramming of pro-inflammatory mediators that may contribute to host tolerance training. These new insights might contribute to the development of novel therapeutic interventions against bacterial infections.

A quorum-sensing signal promotes host tolerance training through HDAC1-mediated epigenetic reprogramming.

The mechanisms by which pathogens evade elimination without affecting host fitness are not well understood. For the pathogen Pseudomonas aeruginosa, this evasion appears to be triggered by excretion of the quorum-sensing molecule 2-aminoacetophenone, which dampens host immune responses and modulates host metabolism, thereby enabling the bacteria to persist at a high burden level. Here, we examined how 2-aminoacetophenone trains host tissues to become tolerant to a high bacterial burden, without compromising host fitness. We found that 2-aminoacetophenone regulates histone deacetylase 1 expression and activity, resulting in hypo-acetylation of lysine 18 of histone H3 at pro-inflammatory cytokine loci. Specifically, 2-aminoacetophenone induced reprogramming of immune cells occurs via alterations in histone acetylation of immune cytokines in vivo and in vitro. This host epigenetic reprograming, which was maintained for up to 7 days, dampened host responses to subsequent exposure to 2-aminoacetophenone or other unrelated pathogen-associated molecules. The process was found to involve a distinct molecular mechanism of host chromatin regulation. Inhibition of histone deacetylase 1 prevented the immunomodulatory effects of 2-aminoacetophenone. These observations provide the first mechanistic example of a quorum-sensing molecule regulating a host epigenome to enable tolerance of infection. These insights have enormous potential for developing preventive treatments against bacterial infections.

TNF-α/IL-10 Ratio Correlates with Burn Severity and May Serve as a Risk Predictor of Increased Susceptibility to Infections.

Severe burn injury renders patients susceptible to multiple infection episodes; however, identifying specific patient groups at high risk remains challenging. Burn-induced inflammatory response dramatically modifies the levels of various cytokines. Whether these changes could predict susceptibility to infections remains unknown. The aim of this study was to determine the early changes in the pro- to anti-inflammatory cytokine ratio and investigate its ability to predict susceptibility to repeated infections after severe burn trauma. The patient population consisted of 34 adult patients having early (≤48 h since injury) blood draws following severe (≥20% total burn surface area (TBSA)) burn injury and suffering from a first infection episode at least 1 day after blood collection. Plasma TNF-α and IL-10 levels were measured to explore the association between the TNF-α/IL-10 ratio, hypersusceptibility to infections, burn size (TBSA), and common severity scores (Acute Physiology and Chronic Health Evaluation II (APACHEII), Baux, modified Baux (R-Baux), Ryan Score, and Abbreviated Burn Severity Index (ABSI)). TNF-α/IL10 plasma ratio measured shortly after burn trauma was inversely correlated with burn size and the injury severity scores investigated, and was predictive of repeated infections (≥3 infection episodes) outcome (AUROC [95%CI] of 0.80 [0.63-0.93]). Early measures of circulating TNF-α/IL10 ratio may be a previously unidentified biomarker associated with burn injury severity and predictive of the risk of hypersusceptibility to repeated infections.

Do standard burn mortality formulae work on a population of severely burned children and adults?

Accurate prediction of mortality following burns is useful as an audit tool, and for providing treatment plan and resource allocation criteria. Common burn formulae (Ryan Score, Abbreviated Burn Severity Index (ABSI), classic and revised Baux) have not been compared with the standard Acute Physiology and Chronic Health Evaluation II (APACHEII) or re-validated in a severely (≥20% total burn surface area) burned population. Furthermore, the revised Baux (R-Baux) has been externally validated thoroughly only once and the pediatric Baux (P-Baux) has yet to be. Using 522 severely burned patients, we show that burn formulae (ABSI, Baux, revised Baux) outperform APACHEII among adults (AUROC increase p<0.001 adults; p>0.5 children). The Ryan Score performs well especially among the most at-risk populations (estimated mortality [90% CI] original versus current study: 33% [26-41%] versus 30.18% [24.25-36.86%] for Ryan Score 2; 87% [78-93%] versus 66.48% [51.31-78.87%] for Ryan Score 3). The R-Baux shows accurate discrimination (AUROC 0.908 [0.869-0.947]) and is well-calibrated. However, the ABSI and P-Baux, although showing high measures of discrimination (AUROC 0.826 [0.737-0.916] and 0.848 [0.758-0.938]) in children), exceedingly overestimates mortality, indicating poor calibration. We highlight challenges in designing and employing scores that are applicable to a wide range of populations.

Prediction of multiple infections after severe burn trauma: a prospective cohort study.

OBJECTIVE: To develop predictive models for early triage of burn patients based on hypersusceptibility to repeated infections. BACKGROUND: Infection remains a major cause of mortality and morbidity after severe trauma, demanding new strategies to combat infections. Models for infection prediction are lacking. METHODS: Secondary analysis of 459 burn patients (≥16 years old) with 20% or more total body surface area burns recruited from 6 US burn centers. We compared blood transcriptomes with a 180-hour cutoff on the injury-to-transcriptome interval of 47 patients (≤1 infection episode) to those of 66 hypersusceptible patients [multiple (≥2) infection episodes (MIE)]. We used LASSO regression to select biomarkers and multivariate logistic regression to built models, accuracy of which were assessed by area under receiver operating characteristic curve (AUROC) and cross-validation. RESULTS: Three predictive models were developed using covariates of (1) clinical characteristics; (2) expression profiles of 14 genomic probes; (3) combining (1) and (2). The genomic and clinical models were highly predictive of MIE status [AUROCGenomic = 0.946 (95% CI: 0.906-0.986); AUROCClinical = 0.864 (CI: 0.794-0.933); AUROCGenomic/AUROCClinical P = 0.044]. Combined model has an increased AUROCCombined of 0.967 (CI: 0.940-0.993) compared with the individual models (AUROCCombined/AUROCClinical P = 0.0069). Hypersusceptible patients show early alterations in immune-related signaling pathways, epigenetic modulation, and chromatin remodeling. CONCLUSIONS: Early triage of burn patients more susceptible to infections can be made using clinical characteristics and/or genomic signatures. Genomic signature suggests new insights into the pathophysiology of hypersusceptibility to infection may lead to novel potential therapeutic or prophylactic targets.

A quorum sensing small volatile molecule promotes antibiotic tolerance in bacteria.

Bacteria can be refractory to antibiotics due to a sub-population of dormant cells, called persisters that are highly tolerant to antibiotic exposure. The low frequency and transience of the antibiotic tolerant "persister" trait has complicated elucidation of the mechanism that controls antibiotic tolerance. In this study, we show that 2' Amino-acetophenone (2-AA), a poorly studied but diagnostically important small, volatile molecule produced by the recalcitrant gram-negative human pathogen Pseudomonas aeruginosa, promotes antibiotic tolerance in response to quorum-sensing (QS) signaling. Our results show that 2-AA mediated persister cell accumulation occurs via alteration of the expression of genes involved in the translational capacity of the cell, including almost all ribosomal protein genes and other translation-related factors. That 2-AA promotes persisters formation also in other emerging multi-drug resistant pathogens, including the non 2-AA producer Acinetobacter baumannii implies that 2-AA may play an important role in the ability of gram-negative bacteria to tolerate antibiotic treatments in polymicrobial infections. Given that the synthesis, excretion and uptake of QS small molecules is a common hallmark of prokaryotes, together with the fact that the translational machinery is highly conserved, we posit that modulation of the translational capacity of the cell via QS molecules, may be a general, widely distributed mechanism that promotes antibiotic tolerance among prokaryotes.

Drosophila Kdm4 demethylases in histone H3 lysine 9 demethylation and ecdysteroid signaling.

The dynamic regulation of chromatin structure by histone post-translational modification is an essential regulatory mechanism that controls global gene transcription. The Kdm4 family of H3K9me2,3 and H3K36me2,3 dual specific histone demethylases has been implicated in development and tumorigenesis. Here we show that Drosophila Kdm4A and Kdm4B are together essential for mediating ecdysteroid hormone signaling during larval development. Loss of Kdm4 genes leads to globally elevated levels of the heterochromatin marker H3K9me2,3 and impedes transcriptional activation of ecdysone response genes, resulting in developmental arrest. We further show that Kdm4A interacts with the Ecdysone Receptor (EcR) and colocalizes with EcR at its target gene promoter. Our studies suggest that Kdm4A may function as a transcriptional co-activator by removing the repressive histone mark H3K9me2,3 from cognate promoters.

Unphosphorylated STAT5A stabilizes heterochromatin and suppresses tumor growth.

Tumor suppressors known to date impede cancer growth by arresting the cell cycle or promoting apoptosis. Here we show that unphosphorylated human STAT5A functions as a tumor suppressor capable of repressing multiple oncogenes via heterochromatin formation. Unphosphorylated STAT5A binds to heterochromatin protein 1α (HP1α) and stabilizes heterochromatin. Expressing unphosphorylated STAT5A or HP1α inhibits colon cancer growth in mouse xenograft models. Transcriptome profiling shows that expressing an unphosphorylatable STAT5A has similar effects to overexpressing HP1α in global gene expression. Notably, the majority of the genes commonly repressed by unphosphorylated STAT5A and HP1α have been implicated in cancer development. Finally, down-regulation, somatic mutations, and deletions of STAT5 genes are found in certain human cancers. These results suggest that unphosphorylated STAT5A may epigenetically suppress tumor growth by promoting heterochromatin formation.

The Birt-Hogg-Dubé tumor suppressor Folliculin negatively regulates ribosomal RNA synthesis.

Birt-Hogg-Dubé syndrome (BHD) is a human cancer disorder caused by mutations in the tumor suppressor gene Folliculin (FLCN) with unknown biological functions. Here, we show that the Drosophila homolog of FLCN, dFLCN (a.k.a. dBHD) localizes to the nucleolus and physically interacts with the 19S proteasomal ATPase, Rpt4, a nucleolar resident and known regulator of rRNA transcription. Downregulation of dFLCN resulted in an increase in nucleolar volume and upregulation of rRNA synthesis, whereas dFLCN overexpression reduced rRNA transcription and counteracted the effects of Rpt4 on rRNA production by preventing the association of Rpt4 with the rDNA locus. We further show that human FLCN exhibited evolutionarily conserved function and that Rpt4 knockdown inhibits the growth of FLCN-deficient human renal cancer cells in mouse xenografts. Our study suggests that FLCN functions as a tumor suppressor by negatively regulating rRNA synthesis.

Global heterochromatin loss: a unifying theory of aging?

The aging field is replete with theories. Over the past years, many distinct, yet overlapping mechanisms have been proposed to explain organismal aging. These include free radicals, loss of heterochromatin, genetically programmed senescence, telomere shortening, genomic instability, nutritional intake and growth signaling, to name a few. The objective of this Point-of-View is to highlight recent progress on the "loss of heterochromatin" model of aging and to propose that epigenetic changes contributing to global heterochromatin loss may underlie the various cellular processes associated with aging.