Multi-stage analysis of gene expression and transcription regulation in C57/B6 mouse liver development

ABSTRACT Hepatitis B virus X (HBX) is essential for the productive infection of hepatitis B virus (HBV) in vivo and has a pleiotropic effect on host cells. We have previously demonstrated that the proteasome complex is a cellular target of HBX, that HBX alters the proteolytic activity of proteasome in vitro, and that inhibition of proteasome leads to enhanced viral replication, suggesting that HBX and proteasome interaction plays a crucial role in the life cycle and pathogenesis of HBV. In the present study, we tested the effect of HBX on the proteasome activities in vivo in a transgenic mouse model in which HBX expression is developmentally regulated by the mouse major urinary promoter in the liver. In addition, microarray analysis was performed to examine the effect of HBX expression on the global gene expression profile of the liver. The results showed that the peptidase activities of the proteasome were reduced in the HBX transgenic mouse liver, whereas the activity of another cellular protease was elevated, suggesting a compensatory mechanism in protein degradation. In the microarray analysis, diverse genes were altered in the HBX mouse livers and the number of genes with significant changes increased progressively with age. Functional clustering showed that a number of genes involved in transcription and cell growth were significantly affected in the HBX mice, possibly accounting for the observed pleiotropic effect of HBX. In particular, insulin-like growth factor-binding protein 1 was down-regulated in the HBX mouse liver. The down-regulation was similarly observed during acute woodchuck hepatitis virus infection. Other changes including up-regulation of proteolysis-related genes may also contribute to the profound alterations of liver functions in HBV infection.

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Evolution of mouse circadian enhancers from transposable elements

Genome Biology ◽

10.1186/s13059-021-02409-9 ◽

2021 ◽

Vol 22 (1) ◽

Author(s):

Julius Judd ◽

Hayley Sanderson ◽

Cédric Feschotte

Keyword(s):

Gene Expression ◽

Transposable Elements ◽

Binding Sites ◽

Mouse Liver ◽

Integration Site ◽

Point Mutations ◽

Regulatory Elements ◽

Circadian Gene ◽

Binding Motifs ◽

Reporter Assays

Abstract Background Transposable elements are increasingly recognized as a source of cis-regulatory variation. Previous studies have revealed that transposons are often bound by transcription factors and some have been co-opted into functional enhancers regulating host gene expression. However, the process by which transposons mature into complex regulatory elements, like enhancers, remains poorly understood. To investigate this process, we examined the contribution of transposons to the cis-regulatory network controlling circadian gene expression in the mouse liver, a well-characterized network serving an important physiological function. Results ChIP-seq analyses reveal that transposons and other repeats contribute ~ 14% of the binding sites for core circadian regulators (CRs) including BMAL1, CLOCK, PER1/2, and CRY1/2, in the mouse liver. RSINE1, an abundant murine-specific SINE, is the only transposon family enriched for CR binding sites across all datasets. Sequence analyses and reporter assays reveal that the circadian regulatory activity of RSINE1 stems from the presence of imperfect CR binding motifs in the ancestral RSINE1 sequence. These motifs matured into canonical motifs through point mutations after transposition. Furthermore, maturation occurred preferentially within elements inserted in the proximity of ancestral CR binding sites. RSINE1 also acquired motifs that recruit nuclear receptors known to cooperate with CRs to regulate circadian gene expression specifically in the liver. Conclusions Our results suggest that the birth of enhancers from transposons is predicated both by the sequence of the transposon and by the cis-regulatory landscape surrounding their genomic integration site.

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Analysis of the Effect of Multi-Row and Multi-Passage Aerodynamic Interaction on the Forced Response Variation in a Compressor Configuration: Part 2 — Effects of Additional Structural Mistuning

Volume 7B: Structures and Dynamics ◽

10.1115/gt2017-63019 ◽

2017 ◽

Cited By ~ 2

Author(s):

Johann Gross ◽

Malte Krack ◽

Harald Schoenenborn

Keyword(s):

Epistemic Uncertainty ◽

Element Model ◽

Forced Response ◽

Aerodynamic Loading ◽

Multi Stage ◽

Blade Row ◽

Random Mistuning ◽

Response Variation ◽

Stage Analysis ◽

Turbomachinery Design

The prediction of aerodynamic blade forcing is a very important topic in turbomachinery design. Usually, the wake from the upstream blade row and the potential field from the downstream blade row are considered as the main causes for excitation, which in conjunction with relative rotation of neighboring blade rows, give rise to dynamic forcing of the blades. In addition to those two mechanisms so-called Tyler-Sofrin (or scattered or spinning) modes, which refer to the acoustic interaction with blade rows further up- or downstream, may have a significant impact on blade forcing. In particular, they lead to considerable blade-to-blade variations of the aerodynamic loading. In part 1 of the paper a study of these effects is performed on the basis of a quasi 3D multi-row and multi-passage compressor configuration. Part 2 of the paper proposes a method to analyze the interaction of the aerodynamic forcing asymmetries with the already well-studied effects of random mistuning stemming from blade-to-blade variations of structural properties. Based on a finite element model of a sector, the equations governing the dynamic behavior of the entire bladed disk can be efficiently derived using substructuring techniques. The disk substructure is assumed as cyclically symmetric, while the blades exhibit structural mistuning and linear aeroelastic coupling. In order to avoid the costly multi-stage analysis, the variation of the aerodynamic loading is treated as an epistemic uncertainty, leading to a stochastic description of the annular force pattern. The effects of structural mistuning and stochastic aerodynamic forcing are first studied separately and then in a combined manner for a blisk of a research compressor without and with aeroelastic coupling.

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