scholarly journals Zfp189 Mediates Stress Resilience Through a CREB-Regulated Transcriptional Network in Prefrontal Cortex

2018 ◽  
Author(s):  
Zachary S. Lorsch ◽  
Peter J. Hamilton ◽  
Aarthi Ramakrishnan ◽  
Eric M. Parise ◽  
William J. Wright ◽  
...  
Keyword(s):  
Gene Network ◽  
Zinc Finger Protein ◽  
Transcriptional Network ◽  
Network Activity ◽  
Stress Resilience ◽  
Prefrontal Cortical ◽  
Transcriptional Reprogramming ◽  
Upstream Regulator ◽  
Downstream Effects ◽  
Transcriptional Changes

SummaryStress resilience involves numerous brain-wide transcriptional changes. Determining the organization and orchestration of these transcriptional events may reveal novel antidepressant targets, but this remains unexplored. Here, we characterize the resilient transcriptome with co-expression analysis and identify a single transcriptionally-active uniquely-resilient gene network. Zfp189, a previously unstudied zinc finger protein, is the top network key driver and its overexpression in prefrontal cortical (PFC) neurons preferentially activates this network, alters neuronal activity and promotes behavioral resilience. CREB, which binds Zfp189, is the top upstream regulator of this network. To probe CREB-Zfp189 interactions as a network regulatory mechanism, we employ CRISPR-mediated locus-specific transcriptional reprogramming to direct CREB selectively to the Zfp189 promoter. This single molecular interaction in PFC neurons recapitulates the pro-resilient Zfp189-dependent downstream effects on gene network activity, electrophysiology and behavior. These findings reveal an essential role for Zfp189 and a CREB-Zfp189 regulatory axis in mediating a central transcriptional network of resilience.

Prediction of Learned Resistance or Helplessness by Hippocampal-Prefrontal Cortical Network Activity during Stress

2021 ◽  
pp. JN-RM-0128-21
Author(s):  
Danilo Benette Marques ◽  
Rafael Naime Ruggiero ◽  
Lezio Soares Bueno-Junior ◽  
Matheus Teixeira Rossignoli ◽  
João Pereira Leite
Keyword(s):  
Cortical Network ◽  
Network Activity ◽  
Prefrontal Cortical

scholarly journals Using nanobiopsy of single brain tumour cells to investigate transcriptional reprogramming during standard treatment.

2019 ◽  
Vol 21 (Supplement_4) ◽  
pp. iv7-iv8
Author(s):  
Marilena Elpidorou ◽  
Paolo Actis ◽  
Lucy Stead
Keyword(s):  
Standard Treatment ◽  
Primary Tumour ◽  
Treatment Resistance ◽  
Treatment Resistant ◽  
Transcriptional Reprogramming ◽  
Cytoplasmic Material ◽  
Novel Technology ◽  
Transcriptional Changes ◽  
Transcriptional Reprogram ◽  
Selection Of

Abstract Glioblastoma (GBM) is an incurable brain cancer because, despite aggressive standard treatment (consisting of surgery, radiation and Temozolomide chemotherapy), 100% of tumours recur. GBM tumours are characterised by significant intratumour heterogeneity, with genotypically or phenotypically distinct subpopulations of cells co-existing within each tumour. However, it is not yet known whether the inevitable recurrence of GBM is owing to Darwinian selection of inherently treatment resistant cells within the primary tumour, or the ability of cells to transcriptional reprogram and acquire treatment resistance properties. Knowing this is fundamental to developing more effective treatment for GBM: should we therapeutically target existing cells or their ability to reprogram? The only way to know this is to profile individual cells longitudinally, which has not been possible until now. Here we present a pioneering technology, known as nanobiopsy, which can longitudinally track the transcriptional profile of single GBM cells through standard treatment. The nanobiopsy allows injection or extraction of cytoplasmic material by electrowetting. We have proved that this technique is able to sample cytoplasmic fractions from cells without killing them, giving us the advantage to capture the transcriptional changes occurring through treatment using optimised scRNA sequencing protocols. We are applying this novel technology to help us identify treatment resistance modes and mechanisms to reveal novel targets for drug development.

scholarly journals Metabolic-State-Dependent Remodeling of the Transcriptome in Response to Anoxia and Subsequent Reoxygenation in Saccharomyces cerevisiae

2006 ◽  
Vol 5 (9) ◽  
pp. 1468-1489 ◽  
Author(s):  
Liang-Chuan Lai ◽  
Alexander L. Kosorukoff ◽  
Patricia V. Burke ◽  
Kurt E. Kwast
Keyword(s):  
Gene Network ◽  
Redox Regulation ◽  
Function Analysis ◽  
Genomic Analysis ◽  
Network Activity ◽  
Metabolic State ◽  
Combinatorial Regulation ◽  
State Dependent ◽  
Mitochondrial Functions ◽  
And Function

ABSTRACT We conducted a comprehensive genomic analysis of the temporal response of yeast to anaerobiosis (six generations) and subsequent aerobic recovery (≈2 generations) to reveal metabolic-state (galactose versus glucose)-dependent differences in gene network activity and function. Analysis of variance showed that far fewer genes responded (raw P value of ≤10−8) to the O2 shifts in glucose (1,603 genes) than in galactose (2,388 genes). Gene network analysis reveals that this difference is due largely to the failure of “stress”-activated networks controlled by Msn2/4, Fhl1, MCB, SCB, PAC, and RRPE to transiently respond to the shift to anaerobiosis in glucose as they did in galactose. After ≈1 generation of anaerobiosis, the response was similar in both media, beginning with the deactivation of Hap1 and Hap2/3/4/5 networks involved in mitochondrial functions and the concomitant derepression of Rox1-regulated networks for carbohydrate catabolism and redox regulation and ending (≥2 generations) with the activation of Upc2- and Mot3-regulated networks involved in sterol and cell wall homeostasis. The response to reoxygenation was rapid (<5 min) and similar in both media, dominated by Yap1 networks involved in oxidative stress/redox regulation and the concomitant activation of heme-regulated ones. Our analyses revealed extensive networks of genes subject to combinatorial regulation by both heme-dependent (e.g., Hap1, Hap2/3/4/5, Rox1, Mot3, and Upc2) and heme-independent (e.g., Yap1, Skn7, and Puf3) factors under these conditions. We also uncover novel functions for several cis-regulatory sites and trans-acting factors and define functional regulons involved in the physiological acclimatization to changes in oxygen availability.

scholarly journals Genomic retargeting of p53 and CTCF is associated with transcriptional changes during oncogenic HRas-induced transformation

2020 ◽  
Vol 3 (1) ◽  
Author(s):  
Michal Schwartz ◽  
Avital Sarusi Portugez ◽  
Bracha Zukerman Attia ◽  
Miriam Tannenbaum ◽  
Leslie Cohen ◽  
...  
Keyword(s):  
Transcription Factors ◽  
Mammary Epithelial Cells ◽  
Regulatory Elements ◽  
Mammary Epithelial ◽  
Spatial Coupling ◽  
Transcriptional Reprogramming ◽  
Transcriptional Alterations ◽  
Human Mammary Epithelial ◽  
Transcriptional Changes ◽  
Major Variation

AbstractGene transcription is regulated by distant regulatory elements via combinatorial binding of transcription factors. It is increasingly recognized that alterations in chromatin state and transcription factor binding in these distant regulatory elements may have key roles in cancer development. Here we focused on the first stages of oncogene-induced carcinogenic transformation, and characterized the regulatory network underlying transcriptional changes associated with this process. Using Hi-C data, we observe spatial coupling between differentially expressed genes and their differentially accessible regulatory elements and reveal two candidate transcription factors, p53 and CTCF, as determinants of transcriptional alterations at the early stages of oncogenic HRas-induced transformation in human mammary epithelial cells. Strikingly, the malignant transcriptional reprograming is promoted by redistribution of chromatin binding of these factors without major variation in their expression level. Our results demonstrate that alterations in the regulatory landscape have a major role in driving oncogene-induced transcriptional reprogramming.

scholarly journals Gene network activity in cultivated primary hepatocytes is highly similar to diseased mammalian liver tissue

2016 ◽  
Vol 90 (10) ◽  
pp. 2513-2529 ◽  
Author(s):  
Patricio Godoy ◽  
Agata Widera ◽  
Wolfgang Schmidt-Heck ◽  
Gisela Campos ◽  
Christoph Meyer ◽  
...  
Keyword(s):  
Liver Tissue ◽  
Gene Network ◽  
Network Activity ◽  
Primary Hepatocytes ◽  
Mammalian Liver
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