NF-Y Dependent Epigenetic Modifications Discriminate between Proliferating and Postmitotic Tissue

The regulation of gene transcription requires posttranslational modifications of histones that, in concert with chromatin remodeling factors, shape the structure of chromatin. It is currently under intense investigation how this structure is modulated, in particular in the context of proliferation and differentiation. Compelling evidence suggests that the transcription factor NF-Y acts as a master regulator of cell cycle progression, activating the transcription of many cell cycle regulatory genes. However, the underlying molecular mechanisms are not yet completely understood. Here we show that NF-Y exerts its effect on transcription through the modulation of the histone “code”. NF-Y colocalizes with nascent RNA, while RNA polymerase II is I phosphorylated on serine 2 of the YSPTSPS repeats within its carboxyterminal domain and histones are carrying modifications that represent activation signals of gene expression (H3K9ac and PAN-H4ac). Comparing postmitotic muscle tissue from normal mice and proliferating muscles from mdx mice, we demonstrate by chromatin immunoprecipitation (ChIP) that NF-Y DNA binding activity correlates with the accumulation of acetylated histones H3 and H4 on promoters of key cell cycle regulatory genes, and with their active transcription. Accordingly, p300 is recruited onto the chromatin of NF-Y target genes in a NF-Y-dependent manner, as demonstrated by Re-ChIP. Conversely, the loss of NF-Y binding correlates with a decrease of acetylated histones, the recruitment of HDAC1, and a repressed heterochromatic state with enrichment of histones carrying modifications known to mediate silencing of gene expression (H3K9me3, H3K27me2 and H4K20me3). As a consequence, NF-Y target genes are downregulated in this context. In conclusion, our data indicate a role of NF-Y in modulating the structure and transcriptional competence of chromatin in vivo and support a model in which NF-Y-dependent histone “code” changes contribute to the proper discrimination between proliferating and postmitotic cells in vivo and in vitro

Chronic pain and sex differences:Women accept and move, while men feel blue

Purpose The aim of this study is to explore differences between male and female patients entering a rehabilitation program at a pain clinic in order to gain a greater understanding of different approaches to be used in rehabilitation. Method 1371 patients referred to a specialty pain rehabilitation clinic, completed sociodemographic and pain related questionnaires. They rated their pain acceptance (CPAQ-8), their kinesiophobia (TSK), the impact of pain in their life (MPI), anxiety and depression levels (HAD) and quality of life scales: the SF-36, LiSat-11, and the EQ-5D. Because of the large sample size of the study, the significance level was set at the p amp;lt;= .01. Results Analysis by t-test showed that when both sexes experience the same pain severity, women report significantly higher activity level, pain acceptance and social support while men report higher kinesiophobia, mood disturbances and lower activity level. Conclusion Pain acceptance (CPAQ-8) and kinesiophobia (TSK) showed the clearest differences between men and women. Pain acceptance and kinesiophobia are behaviorally defined and have the potential to be changed.Funding Agencies|Swedish Association of Local Authorities and Regions (SALAR); Vardal Foundation; RehSAM; AFA insurance, Sweden; Swedish Association for Survivors of Accident and Injury (RTP); Renee Eanders Foundation</p

Comparison of depression care provided in general practice in Norway and the Netherlands: registry-based cohort study (The Norwegian GP-DEP study).

Background Depression is highly prevalent in general practice, and organisation of primary health care probably affects the provision of depression care. General practitioners (GPs) in Norway and the Netherlands fulfil comparable roles. However, primary care teams with a mental health nurse (MHN) supplementing the GP have been established in the Netherlands, but not yet in Norway. In order to explore how the organisation of primary mental care affects care delivery, we aimed to examine the provision of GP depression care across the two countries. Methods Registry-based cohort study comprising new depression episodes in patients aged ≥ 18 years, 2011-2015. The Norwegian sample was drawn from the entire population (national health registries); 297,409 episodes. A representative Dutch sample (Nivel Primary Care Database) was included; 27,362 episodes. Outcomes were follow-up consultation(s) with GP, with GP and/or MHN, and antidepressant prescriptions during 12 months from the start of the depression episode. Differences between countries were estimated using negative binomial and Cox regression models, adjusted for patient gender, age and comorbidity. Results Patients in the Netherlands compared to Norway were less likely to receive GP follow-up consultations, IRR (incidence rate ratio) = 0.73 (95% confidence interval (CI) 0.71-0.74). Differences were greatest among patients aged 18-39 years (adj IRR = 0.64, 0.63-0.66) and 40-59 years (adj IRR = 0.71, 0.69-0.73). When comparing follow-up consultations in GP practices, including MHN consultations in the Netherlands, no cross-national differences were found (IRR = 1.00, 0.98-1.01). But in age-stratified analyses, Dutch patients 60 years and older were more likely to be followed up than their Norwegian counterparts (adj IRR = 1.21, 1.16-1.26). Patients in the Netherlands compared to Norway were more likely to receive antidepressant drugs, adj HR (hazard ratio) = 1.32 (1.30-1.34). Conclusions The observed differences indicate that the organisation of primary mental health care affects the provision of follow-up consultations in Norway and the Netherlands. Clinical studies are needed to explore the impact of team-based care and GP-based care on the quality of depression care and patient outcomes