Faculty Opinions recommendation of Copper ion-sensing transcription factor Mac1p post-translationally controls the degradation of its target gene product Ctr1p.

AbstractElucidating transcription mediated by the glucocorticoid receptor (GR) is crucial for understanding the role of glucocorticoids (GCs) in the treatment of diseases. Podocyte is a useful model for studying GR regulation because GCs are the primary medication for podocytopathy. In this study, we integrated data from transcriptome, transcription factor binding, histone modification, and genome topology. Our data reveals that the GR binds and activates selective regulatory elements in podocyte. The 3D interactome captured by HiChIP facilitates the identification of remote targets of GR. We found that GR in podocyte is enriched at transcriptional interaction hubs and super-enhancers. We further demonstrate that the target gene of the top GR-associated super-enhancer is indispensable to the effective functioning of GC in podocyte. Our findings provided insights into the mechanisms underlying the protective effect of GCs on podocyte, and demonstrate the importance of considering transcriptional interactions in order to fine-map regulatory networks of GR.

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The AML-associated K313 mutation enhances C/EBPα activity by leading to C/EBPα overexpression

Cell Death and Disease ◽

10.1038/s41419-021-03948-6 ◽

2021 ◽

Vol 12 (7) ◽

Author(s):

Ian Edward Gentle ◽

Isabel Moelter ◽

Mohamed Tarek Badr ◽

Konstanze Döhner ◽

Michael Lübbert ◽

...

Keyword(s):

Gene Expression ◽

Cell Culture ◽

Transcription Factor ◽

Transcription Factors ◽

Transcriptional Activity ◽

Target Gene ◽

Wild Type ◽

Elevated Expression ◽

Factor C ◽

Acute Myeloid

AbstractMutations in the transcription factor C/EBPα are found in ~10% of all acute myeloid leukaemia (AML) cases but the contribution of these mutations to leukemogenesis is incompletely understood. We here use a mouse model of granulocyte progenitors expressing conditionally active HoxB8 to assess the cell biological and molecular activity of C/EBPα-mutations associated with human AML. Both N-terminal truncation and C-terminal AML-associated mutations of C/EBPα substantially altered differentiation of progenitors into mature neutrophils in cell culture. Closer analysis of the C/EBPα-K313-duplication showed expansion and prolonged survival of mutant C/EBPα-expressing granulocytes following adoptive transfer into mice. C/EBPα-protein containing the K313-mutation further showed strongly enhanced transcriptional activity compared with the wild-type protein at certain promoters. Analysis of differentially regulated genes in cells overexpressing C/EBPα-K313 indicates a strong correlation with genes regulated by C/EBPα. Analysis of transcription factor enrichment in the differentially regulated genes indicated a strong reliance of SPI1/PU.1, suggesting that despite reduced DNA binding, C/EBPα-K313 is active in regulating target gene expression and acts largely through a network of other transcription factors. Strikingly, the K313 mutation caused strongly elevated expression of C/EBPα-protein, which could also be seen in primary K313 mutated AML blasts, explaining the enhanced C/EBPα activity in K313-expressing cells.

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Identification of genes, pathways and transcription factor-miRNA-target gene networks and experimental verification in venous thromboembolism

Scientific Reports ◽

10.1038/s41598-021-95909-4 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Yiming Su ◽

Qiyi Li ◽

Zhiyong Zheng ◽

Xiaomin Wei ◽

Peiyong Hou

Keyword(s):

Transcription Factor ◽

Venous Thromboembolism ◽

Cellular Response ◽

Gene Network ◽

Mirna Target ◽

Target Gene ◽

Vascular Endothelial Cell ◽

Differentially Expressed ◽

Ppi Network ◽

Mirna Target Gene

AbstractVenous thromboembolism (VTE) is a complex, multifactorial life-threatening disease that involves vascular endothelial cell (VEC) dysfunction. However, the exact pathogenesis and underlying mechanisms of VTE are not completely clear. The aim of this study was to identify the core genes and pathways in VECs that are involved in the development and progression of unprovoked VTE (uVTE). The microarray dataset GSE118259 was downloaded from the Gene Expression Omnibus database, and 341 up-regulated and 8 down-regulated genes were identified in the VTE patients relative to the healthy controls, including CREB1, HIF1α, CBL, ILK, ESM1 and the ribosomal protein family genes. The protein–protein interaction (PPI) network and the transcription factor (TF)-miRNA-target gene network were constructed with these differentially expressed genes (DEGs), and visualized using Cytoscape software 3.6.1. Eighty-nine miRNAs were predicted as the targeting miRNAs of the DEGs, and 197 TFs were predicted as regulators of these miRNAs. In addition, 237 node genes and 4 modules were identified in the PPI network. The significantly enriched pathways included metabolic, cell adhesion, cell proliferation and cellular response to growth factor stimulus pathways. CREB1 was a differentially expressed TF in the TF-miRNA-target gene network, which regulated six miRNA-target gene pairs. The up-regulation of ESM1, HIF1α and CREB1 was confirmed at the mRNA and protein level in the plasma of uVTE patients. Taken together, ESM1, HIF1α and the CREB1-miRNA-target genes axis play potential mechanistic roles in uVTE development.

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