Expression of the circadian clock gene Period2 in the hippocampus: possible implications for synaptic plasticity and learned behaviour

Genes responsible for generating circadian oscillations are expressed in a variety of brain regions not typically associated with circadian timing. The functions of this clock gene expression are largely unknown, and in the present study we sought to explore the role of the Per2 (Period 2) gene in hippocampal physiology and learned behaviour. We found that PER2 protein is highly expressed in hippocampal pyramidal cell layers and that the expression of both protein and mRNA varies with a circadian rhythm. The peaks of these rhythms occur in the late night or early morning and are almost 180° out-of-phase with the expression rhythms measured from the suprachiasmatic nucleus of the same animals. The rhythms in Per2 expression are autonomous as they are present in isolated hippocampal slices maintained in culture. Physiologically, Per2-mutant mice exhibit abnormal long-term potentiation. The underlying mechanism is suggested by the finding that levels of phosphorylated cAMP-response-element-binding protein, but not phosphorylated extracellular-signal-regulated kinase, are reduced in hippocampal tissue from mutant mice. Finally, Per2-mutant mice exhibit deficits in the recall of trace, but not cued, fear conditioning. Taken together, these results provide evidence that hippocampal cells contain an autonomous circadian clock. Furthermore, the clock gene Per2 may play a role in the regulation of long-term potentiation and in the recall of some forms of learned behaviour

Out FOXing Parkinson Disease: Where Development Meets Neurodegeneration

The central survival role of FOX proteins may allow a unified view of the genetic and environmental factors that cause Parkinson disease

APOLO-Bari, an internet-based program for longitudinal support of bariatric surgery patients: study protocol for a randomized controlled trial

Background: Despite evidence of successful weight loss for bariatric surgery patients, some patients experience considerable weight regain over the long term. Given the strong association between post-surgery health behaviors and outcomes, aftercare intervention to address key behaviors appears to be a reasonable relapse-prevention strategy. As the burden of obesity rates increases in healthcare centers, an internet-based program appears to be a reasonable strategy for supporting bariatric surgery patients in the long term. The primary purpose of the current project is to develop and test the efficacy and perceived utility of APOLO-Bari.Methods/design: This study is a randomized control trial, which will be conducted in two hospital centers in the North of Portugal; it includes a control group receiving treatment as usual and an intervention group receiving the APOLO-Bari program for one year in addition to treatment as usual. A total of 180 male and female participants who underwent bariatric surgery (gastric sleeve or gastric bypass surgery) for 12 to 20 months will be recruited. Both groups will complete a similar set of questionnaires at baseline, every 4 months until the end of the intervention, and at 6 and 12 months follow-up. Assessment includes anthropometric variables and psychological self-report measures. The primary outcome measure will be weight regain measured at the end of treatment, and at 6 and 12 months follow-up. The secondary aims are to test the cost-effectiveness of the intervention and to investigate psychological predictors and trajectories of weight regain. APOLO-Bari was developed to address the weight regain problem in the bariatric population by offering additional guidance to bariatric patients during the postoperative period. The program includes: (a) a psychoeducational cognitive-behavioral-based self-help manual, (b) a weekly feedback messaging system that sends a feedback statement related to information reported by the participant, and (c) interactive chat sessions scheduled witThis research was partially supported by the Fundacao para a Ciencia e a Tecnologia through a European Union COMPETE program grant to Eva Conceicao (IF/01219/2014 and PTDC/MHC-PCL/4974/2012), a doctoral scholarship to Ana Pinto-Bastos (SFRH/BD/104159/2014), a doctoral scholarship to Sofia Ramalho (SFRH/BD/104182/2014), and a postdoctoral scholarship to Ana Rita Vaz (SFRH/BPD/94490/2013), co-financed by FEDER under the PT2020 Partnership Agreement (UID/PSI/01662/2013).info:eu-repo/semantics/publishedVersio

Genome-Wide Profiling of H3K56 Acetylation and Transcription Factor Binding Sites in Human Adipocytes

The growing epidemic of obesity and metabolic diseases calls for a better understanding of adipocyte biology. The regulation of transcription in adipocytes is particularly important, as it is a target for several therapeutic approaches. Transcriptional outcomes are influenced by both histone modifications and transcription factor binding. Although the epigenetic states and binding sites of several important transcription factors have been profiled in the mouse 3T3-L1 cell line, such data are lacking in human adipocytes. In this study, we identified H3K56 acetylation sites in human adipocytes derived from mesenchymal stem cells. H3K56 is acetylated by CBP and p300, and deacetylated by SIRT1, all are proteins with important roles in diabetes and insulin signaling. We found that while almost half of the genome shows signs of H3K56 acetylation, the highest level of H3K56 acetylation is associated with transcription factors and proteins in the adipokine signaling and Type II Diabetes pathways. In order to discover the transcription factors that recruit acetyltransferases and deacetylases to sites of H3K56 acetylation, we analyzed DNA sequences near H3K56 acetylated regions and found that the E2F recognition sequence was enriched. Using chromatin immunoprecipitation followed by high-throughput sequencing, we confirmed that genes bound by E2F4, as well as those by HSF-1 and C/EBPα, have higher than expected levels of H3K56 acetylation, and that the transcription factor binding sites and acetylation sites are often adjacent but rarely overlap. We also discovered a significant difference between bound targets of C/EBPα in 3T3-L1 and human adipocytes, highlighting the need to construct species-specific epigenetic and transcription factor binding site maps. This is the first genome-wide profile of H3K56 acetylation, E2F4, C/EBPα and HSF-1 binding in human adipocytes, and will serve as an important resource for better understanding adipocyte transcriptional regulation.Singapore. Agency for Science, Technology and Research (National Science Scholarship )Massachusetts Institute of Technology (Eugene Bell Career Development Chair)National Science Foundation (U.S.) (Award No. DBI-0821391)Pfizer Inc

Multistable Decision Switches for Flexible Control of Epigenetic Differentiation

It is now recognized that molecular circuits with positive feedback can induce two different gene expression states (bistability) under the very same cellular conditions. Whether, and how, cells make use of the coexistence of a larger number of stable states (multistability) is however largely unknown. Here, we first examine how autoregulation, a common attribute of genetic master regulators, facilitates multistability in two-component circuits. A systematic exploration of these modules' parameter space reveals two classes of molecular switches, involving transitions in bistable (progression switches) or multistable (decision switches) regimes. We demonstrate the potential of decision switches for multifaceted stimulus processing, including strength, duration, and flexible discrimination. These tasks enhance response specificity, help to store short-term memories of recent signaling events, stabilize transient gene expression, and enable stochastic fate commitment. The relevance of these circuits is further supported by biological data, because we find them in numerous developmental scenarios. Indeed, many of the presented information-processing features of decision switches could ultimately demonstrate a more flexible control of epigenetic differentiation

Epistasis of Transcriptomes Reveals Synergism between Transcriptional Activators Hnf1α and Hnf4α

The transcription of individual genes is determined by combinatorial interactions between DNA–binding transcription factors. The current challenge is to understand how such combinatorial interactions regulate broad genetic programs that underlie cellular functions and disease. The transcription factors Hnf1α and Hnf4α control pancreatic islet β-cell function and growth, and mutations in their genes cause closely related forms of diabetes. We have now exploited genetic epistasis to examine how Hnf1α and Hnf4α functionally interact in pancreatic islets. Expression profiling in islets from either Hnf1a+/− or pancreas-specific Hnf4a mutant mice showed that the two transcription factors regulate a strikingly similar set of genes. We integrated expression and genomic binding studies and show that the shared transcriptional phenotype of these two mutant models is linked to common direct targets, rather than to known effects of Hnf1α on Hnf4a gene transcription. Epistasis analysis with transcriptomes of single- and double-mutant islets revealed that Hnf1α and Hnf4α regulate common targets synergistically. Hnf1α binding in Hnf4a-deficient islets was decreased in selected targets, but remained unaltered in others, thus suggesting that the mechanisms for synergistic regulation are gene-specific. These findings provide an in vivo strategy to study combinatorial gene regulation and reveal how Hnf1α and Hnf4α control a common islet-cell regulatory program that is defective in human monogenic diabetes