USE OF APRIORI KNOWLEDGE ON DYNAMIC BAYESIAN MODELS IN TIME-COURSE EXPRESSION DATA PREDICTION

Indiana University-Purdue University Indianapolis (IUPUI)Bayesian networks, one of the most widely used techniques to understand or predict the future by making use of current or previous data, have gained credence over the last decade for their ability to simulate large gene expression datasets to track and predict the reasons for changes in biological systems. In this work, we present a dynamic Bayesian model with gene annotation scores such as the gene characterization index (GCI) and the GenCards inferred functionality score (GIFtS) to understand and assess the prediction performance of the model by incorporating prior knowledge. Time-course breast cancer data including expression data about the genes in the breast cell-lines when treated with doxorubicin is considered for this study. Bayes server software was used for the simulations in a dynamic Bayesian environment with 8 and 19 genes on 12 different data combinations for each category of gene set to predict and understand the future time- course expression profiles when annotation scores are incorporated into the model. The 8-gene set predicted the next time course with r>0.95, and the 19-gene set yielded a value of r>0.8 in 92% cases of the simulation experiments. These results showed that incorporating prior knowledge into the dynamic Bayesian model for simulating the time- course expression data can improve the prediction performance when sufficient apriori parameters are provided

Functional Coordination of BET Family Proteins Underlies Altered Transcription Associated With Memory Impairment in Fragile X Syndrome

Bromodomain and extraterminal proteins (BET) are epigenetic readers that play critical roles in gene regulation. Pharmacologic inhibition of the bromodomain present in all BET family members is a promising therapeutic strategy for various diseases, but its impact on individual family members has not been well understood. Using a transcriptional induction paradigm in neurons, we have systematically demonstrated that three major BET family proteins (BRD2/3/4) participated in transcription with different recruitment kinetics, interdependency, and sensitivity to a bromodomain inhibitor, JQ1. In a mouse model of fragile X syndrome (FXS), BRD2/3 and BRD4 showed oppositely altered expression and chromatin binding, correlating with transcriptional dysregulation. Acute inhibition of CBP/p300 histone acetyltransferase (HAT) activity restored the altered binding patterns of BRD2 and BRD4 and rescued memory impairment in FXS. Our study emphasizes the importance of understanding the BET coordination controlled by a balanced action between HATs with different substrate specificity

Temporal Control of Metabolic Amplitude by Nocturnin

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An Intrinsic Transcriptional Program Underlying Synaptic Scaling during Activity Suppression

Homeostatic scaling allows neurons to maintain stable activity patterns by globally altering their synaptic strength in response to changing activity levels. Suppression of activity by the blocking of action potentials increases synaptic strength through an upregulation of surface α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors. Although this synaptic upscaling was shown to require transcription, the molecular nature of the intrinsic transcription program underlying this process and its functional significance have been unclear. Using RNA-seq, we identified 73 genes that were specifically upregulated in response to activity suppression. In particular, Neuronal pentraxin-1 (Nptx1) increased within 6 hr of activity blockade, and knockdown of this gene blocked the increase in synaptic strength. Nptx1 induction is mediated by calcium influx through the T-type voltage-gated calcium channel, as well as two transcription factors, SRF and ELK1. Altogether, these results uncover a transcriptional program that specifically operates when neuronal activity is suppressed to globally coordinate the increase in synaptic strength

Reprogramming of Polycomb-Mediated Gene Silencing in Embryonic Stem Cells by the miR-290 Family and the Methyltransferase Ash1l

Members of the miR-290 family are the most abundantly expressed microRNAs (miRNAs) in mouse embryonic stem cells (ESCs). They regulate aspects of differentiation, pluripotency, and proliferation of ESCs, but the molecular program that they control has not been fully delineated. In the absence of Dicer, ESCs fail to express mature miR-290 miRNAs and have selective aberrant overexpression of Hoxa, Hoxb, Hoxc, and Hoxd genes essential for body plan patterning during embryogenesis, but they do not undergo a full differentiation program. Introduction of mature miR-291 into DCR−/− ESCs restores Hox gene silencing. This was attributed to the unexpected regulation of Polycomb-mediated gene targeting by miR-291. We identified the methyltransferase Ash1l as a pivotal target of miR-291 mediating this effect. Collectively, our data shed light on the role of Dicer in ESC homeostasis by revealing a facet of molecular regulation by the miR-290 family

The malaria parasite has an intrinsic clock

Copyright © 2020 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works http://www.sciencemag.org/about/science-licenses-journal-article-reuseThis is an article distributed under the terms of the Science Journals Default License.Malarial rhythmic fevers are the consequence of the synchronous bursting of red blood cells (RBCs) on completion of the malaria parasite asexual cell cycle. Here, we hypothesized that an intrinsic clock in the parasite Plasmodium chabaudi underlies the 24-hour-based rhythms of RBC bursting in mice. We show that parasite rhythms are flexible and lengthen to match the rhythms of hosts with long circadian periods. We also show that malaria rhythms persist even when host food intake is evenly spread across 24 hours, suggesting that host feeding cues are not required for synchrony. Moreover, we find that the parasite population remains synchronous and rhythmic even in an arrhythmic clock mutant host. Thus, we propose that parasite rhythms are generated by the parasite, possibly to anticipate its circadian environment.F.R.-F. is an Associate, I.K. is a Lab Manager II, and J.S.T. is an Investigator in the Howard Hughes Medical Institute. J.H.A. is supported by NIH NIA F32-AG064886 and NIH T32-HLO9701; E.B.K. by NIH R01-HL128538, K24-HL105664, and P01-AG009975 and the MGH Department of Neurology; and M.M.M. by PTDC/BIA-MOL/30112/2017 and PTDC/MED-IMU/28664/2017. M.M.M. is supported by FCT grants (PTDC/BIA-MOL/30112/2017 and PTDC/MED-IMU/28664/2017) and F.R.-F. by NIH NIGMS 1K99GM132557-01info:eu-repo/semantics/publishedVersio