RNA transcripts from WT or Bmal1-deficient blood-brain barrier throughout a 24 hr period
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE135874 | GEO | 2020/12/01
REPOSITORIES: GEO
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Project description:The blood-brain barrier (BBB) is an evolutionary conserved tissue interface that possesses potent chemical protection properties functioning to strictly modulate the central nervous system (CNS) microenvironment. These same properties, including tight cellular junctions and efflux transporters, also limit access of CNS-active pharmaceuticals. For this reason, understanding the molecular mechanisms that regulate BBB chemical protection is of great biomedical interest. The BBB of Drosophila consists of two surface glia layers that completely surround the brain. This tissue interface contains both “tight” cellular junctions (termed septate junctions) and drug efflux transporters; thus, the Drosophila BBB can potentially serve as a model for understanding complex regulation of BBB physiology. In this study, we show reciprocal compensatory responses following disruption of critical BBB genes: deletion of the septate junction regulator Moody causes increased drug efflux and up-regulation of the P-glycoprotein ortholog Mdr65; conversely, disruption of Mdr65 expression causes increased septate junction tightness and up-regulation of Moody. We reveal these homeostatic interactions with physiologic observations, gene expression data, and anatomical images of the BBB surface. Whole brain microarray data point to responses that are consistent with our physiologic observations and these responses are likely localized to the BBB. To our knowledge, this is the first observation of a reciprocal compensatory interaction at a tissue barrier. Furthermore, this study paves the way for future studies elucidating the direct pathways that link GPCR signaling and drug transporter regulation at the BBB. The main comparisons are between WT_new, C17 (Moody null), and PMdr65 (Mdr65 null). Since WT_new were processed on a different day than C17 and PMdr65, we also included another WT sample (WT_old) to control for genes that change depending on batch effects. Since the mutants are also in a different genetic background than WT, we also included a control that is in a similar background (UAS_control).
2013-12-31 | E-GEOD-46550 | biostudies-arrayexpress
Project description:The blood-brain barrier (BBB) is an evolutionary conserved tissue interface that possesses potent chemical protection properties functioning to strictly modulate the central nervous system (CNS) microenvironment. These same properties, including tight cellular junctions and efflux transporters, also limit access of CNS-active pharmaceuticals. For this reason, understanding the molecular mechanisms that regulate BBB chemical protection is of great biomedical interest. The BBB of Drosophila consists of two surface glia layers that completely surround the brain. This tissue interface contains both “tight” cellular junctions (termed septate junctions) and drug efflux transporters; thus, the Drosophila BBB can potentially serve as a model for understanding complex regulation of BBB physiology. In this study, we show reciprocal compensatory responses following disruption of critical BBB genes: deletion of the septate junction regulator Moody causes increased drug efflux and up-regulation of the P-glycoprotein ortholog Mdr65; conversely, disruption of Mdr65 expression causes increased septate junction tightness and up-regulation of Moody. We reveal these homeostatic interactions with physiologic observations, gene expression data, and anatomical images of the BBB surface. Whole brain microarray data point to responses that are consistent with our physiologic observations and these responses are likely localized to the BBB. To our knowledge, this is the first observation of a reciprocal compensatory interaction at a tissue barrier. Furthermore, this study paves the way for future studies elucidating the direct pathways that link GPCR signaling and drug transporter regulation at the BBB.
2013-12-31 | GSE46550 | GEO
Project description:Eukaryotic circadian clocks include transcriptional/translational feedback loops that drive 24-hour rhythms of transcription.These transcriptional rhythms underlie oscillations of protein abundance, thereby mediating circadian rhythms of behavior, physiology, and metabolism. Numerous studies over the last decade have employed microarrays to profile circadian transcriptional rhythms in various organisms and tissues. Here we use RNA sequencing (RNA-Seq) to profile the circadian transcriptome of *Drosophila melanogaster* brain from wild-type and *period*-null clock-defective animals. We identify several hundred transcripts whose abundance oscillates with 24-hour periods, including a number of non-coding RNAs (ncRNAs) that were not identified in previous microarray studies. Of particular interest are *U snoRNA host genes* (*Uhgs*), a family of cycling ncRNAs that encode the precursors of over 50 box C/D snoRNAs, key regulators of ribosomal biogenesis. Transcriptional profiling at the level of individual exons reveals alternative splice isoforms for many genes whose relative abundances are regulated by either *period* or circadian time, although the effect of circadian time is muted in comparison to that of *period*. Interestingly, *period* loss-of-function significantly alters the frequency of RNA editing at a number of editing sites, suggesting an unexpected link between a key circadian gene and RNA editing. We also identify tens of thousands of novel splicing events beyond those previously annotated by the modENCODE consortium, including several that affect key circadian genes. These studies demonstrate extensive circadian control of ncRNA expression, reveal the extent of clock control of alternative splicing and RNA editing, and provide a novel, genome-wide map of splicing in *Drosophila* brain. RNA-Seq transcriptional profiling of Drosophila brains from wildtype and period loss-of-function (per0) flies with time points taken over two days in constant darkness. Time points at CT24, 28, 32, 36, 40, 44, 48, 52, 56, 60, 64, and 68. 10-12 brains per time point.
2012-03-27 | E-GEOD-36108 | biostudies-arrayexpress
Project description:Eukaryotic circadian clocks include transcriptional/translational feedback loops that drive 24-hour rhythms of transcription.These transcriptional rhythms underlie oscillations of protein abundance, thereby mediating circadian rhythms of behavior, physiology, and metabolism. Numerous studies over the last decade have employed microarrays to profile circadian transcriptional rhythms in various organisms and tissues. Here we use RNA sequencing (RNA-Seq) to profile the circadian transcriptome of *Drosophila melanogaster* brain from wild-type and *period*-null clock-defective animals. We identify several hundred transcripts whose abundance oscillates with 24-hour periods, including a number of non-coding RNAs (ncRNAs) that were not identified in previous microarray studies. Of particular interest are *U snoRNA host genes* (*Uhgs*), a family of cycling ncRNAs that encode the precursors of over 50 box C/D snoRNAs, key regulators of ribosomal biogenesis. Transcriptional profiling at the level of individual exons reveals alternative splice isoforms for many genes whose relative abundances are regulated by either *period* or circadian time, although the effect of circadian time is muted in comparison to that of *period*. Interestingly, *period* loss-of-function significantly alters the frequency of RNA editing at a number of editing sites, suggesting an unexpected link between a key circadian gene and RNA editing. We also identify tens of thousands of novel splicing events beyond those previously annotated by the modENCODE consortium, including several that affect key circadian genes. These studies demonstrate extensive circadian control of ncRNA expression, reveal the extent of clock control of alternative splicing and RNA editing, and provide a novel, genome-wide map of splicing in *Drosophila* brain.
2012-03-27 | GSE36108 | GEO
Project description:Over the past decade, genome-wide assays have underscored the broad sweep of circadian gene expression. A substantial fraction of the transcriptome undergoes oscillations in many organisms and tissues, which governs the many biochemical, physiological and behavioral functions under circadian control. Based predominantly on the transcription feedback loops important for core circadian timekeeping, it is commonly assumed that this widespread mRNA cycling reflects circadian transcriptional cycling. To address this issue, we directly measured dynamic changes in mouse liver transcription using Nascent-Seq. Many genes are rhythmically transcribed over the 24h day, which include precursors of several non-coding RNAs as well as the expected set of core clock genes. Surprisingly however, nascent RNA rhythms overlap poorly with mRNA abundance rhythms assayed by RNA-seq. This is because most mouse liver genes with rhythmic mRNA expression manifest poor transcriptional rhythms, indicating a prominent role of post-transcriptional regulation in setting mRNA cycling amplitude. To gain further insight into circadian transcriptional regulation, we also characterized the rhythmic transcription of liver genes targeted by the transcription factors CLOCK and BMAL1; they directly target other core clock genes and sit at the top of the molecular circadian clock hierarchy in mammals. CLK:BMAL1 rhythmically bind at the same discrete phase of the circadian cycle to all target genes, which not surprisingly have a much higher percentage of rhythmic transcription than the genome as a whole. However, there is a surprisingly heterogeneous set of cycling transcription phases of direct target genes, which even include core clock genes. This indicates a disconnect between rhythmic DNA binding and the peak of transcription, which is likely due to other transcription factors that collaborate with CLK:BMAL1. In summary, the application of Nascent-Seq to a mammalian tissue provides surprising insights into the rhythmic control of gene expression and should have broad applications beyond the analysis of circadian rhythms. CLK and BMAL1 DNA binding profile in the mouse liver at ZT8, sequenced along an Input sample using GAII (ChIP-Seq) Supplementary file ChIPSeq_Mouse_Liver_Processed_data_Table1.txt represents annotated CLK and BMAL1 peaks.
2012-11-10 | E-GEOD-36874 | biostudies-arrayexpress
Project description:Circadian rhythms are generated by an auto-regulatory feedback loop composed of transcriptional activators and repressors. Disruption of circadian rhythms contributes to Type 2 diabetes (T2D) pathogenesis. We elucidated whether altered circadian rhythmicity of clock genes is associated with metabolic dysfunction in T2D. Transcriptional cycling of core clock genes BMAL1, CLOCK, and PER3 was altered in skeletal muscle from individuals with T2D and this was coupled with reduced number and amplitude of cycling genes and disturbed circadian oxygen consumption. Inner-mitochondria associated genes were enriched for rhythmic peaks in NGT, but not T2D, and positively correlated with insulin sensitivity. ChIP-sequencing identified CLOCK and BMAL1 binding to inner-mitochondrial genes associated with insulin sensitivity, implicating regulation by the core clock. Inner-mitochondria disruption altered core-clock gene expression and free-radical production, phenomena that were restored by resveratrol treatment. We identify bi-directional communication between mitochondrial function and rhythmic gene expression, processes which are disturbed in diabetes.
2021-08-17 | GSE182120 | GEO
Project description:Circadian rhythms are generated by an auto-regulatory feedback loop composed of transcriptional activators and repressors. Disruption of circadian rhythms contributes to Type 2 diabetes (T2D) pathogenesis. We elucidated whether altered circadian rhythmicity of clock genes is associated with metabolic dysfunction in T2D. Transcriptional cycling of core clock genes BMAL1, CLOCK, and PER3 was altered in skeletal muscle from individuals with T2D and this was coupled with reduced number and amplitude of cycling genes and disturbed circadian oxygen consumption. Inner-mitochondria associated genes were enriched for rhythmic peaks in NGT, but not T2D, and positively correlated with insulin sensitivity. ChIP-sequencing identified CLOCK and BMAL1 binding to inner-mitochondrial genes associated with insulin sensitivity, implicating regulation by the core clock. Inner-mitochondria disruption altered core-clock gene expression and free-radical production, phenomena that were restored by resveratrol treatment. We identify bi-directional communication between mitochondrial function and rhythmic gene expression, processes which are disturbed in diabetes.
2021-08-17 | GSE182117 | GEO
Project description:Over the past decade, genome-wide assays have underscored the broad sweep of circadian gene expression. A substantial fraction of the transcriptome undergoes oscillations in many organisms and tissues, which governs the many biochemical, physiological and behavioral functions under circadian control. Based predominantly on the transcription feedback loops important for core circadian timekeeping, it is commonly assumed that this widespread mRNA cycling reflects circadian transcriptional cycling. To address this issue, we directly measured dynamic changes in mouse liver transcription using Nascent-Seq. Many genes are rhythmically transcribed over the 24h day, which include precursors of several non-coding RNAs as well as the expected set of core clock genes. Surprisingly however, nascent RNA rhythms overlap poorly with mRNA abundance rhythms assayed by RNA-seq. This is because most mouse liver genes with rhythmic mRNA expression manifest poor transcriptional rhythms, indicating a prominent role of post-transcriptional regulation in setting mRNA cycling amplitude. To gain further insight into circadian transcriptional regulation, we also characterized the rhythmic transcription of liver genes targeted by the transcription factors CLOCK and BMAL1; they directly target other core clock genes and sit at the top of the molecular circadian clock hierarchy in mammals. CLK:BMAL1 rhythmically bind at the same discrete phase of the circadian cycle to all target genes, which not surprisingly have a much higher percentage of rhythmic transcription than the genome as a whole. However, there is a surprisingly heterogeneous set of cycling transcription phases of direct target genes, which even include core clock genes. This indicates a disconnect between rhythmic DNA binding and the peak of transcription, which is likely due to other transcription factors that collaborate with CLK:BMAL1. In summary, the application of Nascent-Seq to a mammalian tissue provides surprising insights into the rhythmic control of gene expression and should have broad applications beyond the analysis of circadian rhythms.
2012-11-10 | GSE36872 | GEO
Project description:Over the past decade, genome-wide assays have underscored the broad sweep of circadian gene expression. A substantial fraction of the transcriptome undergoes oscillations in many organisms and tissues, which governs the many biochemical, physiological and behavioral functions under circadian control. Based predominantly on the transcription feedback loops important for core circadian timekeeping, it is commonly assumed that this widespread mRNA cycling reflects circadian transcriptional cycling. To address this issue, we directly measured dynamic changes in mouse liver transcription using Nascent-Seq. Many genes are rhythmically transcribed over the 24h day, which include precursors of several non-coding RNAs as well as the expected set of core clock genes. Surprisingly however, nascent RNA rhythms overlap poorly with mRNA abundance rhythms assayed by RNA-seq. This is because most mouse liver genes with rhythmic mRNA expression manifest poor transcriptional rhythms, indicating a prominent role of post-transcriptional regulation in setting mRNA cycling amplitude. To gain further insight into circadian transcriptional regulation, we also characterized the rhythmic transcription of liver genes targeted by the transcription factors CLOCK and BMAL1; they directly target other core clock genes and sit at the top of the molecular circadian clock hierarchy in mammals. CLK:BMAL1 rhythmically bind at the same discrete phase of the circadian cycle to all target genes, which not surprisingly have a much higher percentage of rhythmic transcription than the genome as a whole. However, there is a surprisingly heterogeneous set of cycling transcription phases of direct target genes, which even include core clock genes. This indicates a disconnect between rhythmic DNA binding and the peak of transcription, which is likely due to other transcription factors that collaborate with CLK:BMAL1. In summary, the application of Nascent-Seq to a mammalian tissue provides surprising insights into the rhythmic control of gene expression and should have broad applications beyond the analysis of circadian rhythms.
2012-11-10 | GSE36871 | GEO
Project description:Over the past decade, genome-wide assays have underscored the broad sweep of circadian gene expression. A substantial fraction of the transcriptome undergoes oscillations in many organisms and tissues, which governs the many biochemical, physiological and behavioral functions under circadian control. Based predominantly on the transcription feedback loops important for core circadian timekeeping, it is commonly assumed that this widespread mRNA cycling reflects circadian transcriptional cycling. To address this issue, we directly measured dynamic changes in mouse liver transcription using Nascent-Seq. Many genes are rhythmically transcribed over the 24h day, which include precursors of several non-coding RNAs as well as the expected set of core clock genes. Surprisingly however, nascent RNA rhythms overlap poorly with mRNA abundance rhythms assayed by RNA-seq. This is because most mouse liver genes with rhythmic mRNA expression manifest poor transcriptional rhythms, indicating a prominent role of post-transcriptional regulation in setting mRNA cycling amplitude. To gain further insight into circadian transcriptional regulation, we also characterized the rhythmic transcription of liver genes targeted by the transcription factors CLOCK and BMAL1; they directly target other core clock genes and sit at the top of the molecular circadian clock hierarchy in mammals. CLK:BMAL1 rhythmically bind at the same discrete phase of the circadian cycle to all target genes, which not surprisingly have a much higher percentage of rhythmic transcription than the genome as a whole. However, there is a surprisingly heterogeneous set of cycling transcription phases of direct target genes, which even include core clock genes. This indicates a disconnect between rhythmic DNA binding and the peak of transcription, which is likely due to other transcription factors that collaborate with CLK:BMAL1. In summary, the application of Nascent-Seq to a mammalian tissue provides surprising insights into the rhythmic control of gene expression and should have broad applications beyond the analysis of circadian rhythms.
2012-11-10 | GSE36874 | GEO