Rack1 is Essential for Corticogenesis by Preventing P21-Dependent Senescence in Neural Stem Cells
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus Musculus
SUBMITTER: 
Haitao Wu
PROVIDER: PXD027798 | iProX | Mon Aug 09 00:00:00 BST 2021
REPOSITORIES: iProX
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Project description:Epigenetic regulation is essential for the normal development of human cerebral cortex, and its disruptions would lead to diverse neurodevelopmental disorders. The epigenetic co-repressor CDYL exhibits widespread expression across various cell clusters within the human embryonic cortex, yet its roles in this intricate process have remained elusive. Here, we show that CDYL is critical for cortical neurogenesis, and CDYL deficiency led to an augmentation in the generation of GABAergic neurons instead of cortical progenitors and neurons in the cortical organoid model. Combining analysis of bulk RNA-seq and ChIP seq, we identified NNAT as a significant CDYL target by H3K27me3 modification, crucial for the fate determination of neural stem cells within human cortical organoids, distinctly diverging from the murine cortex at a similar developmental stage. Collectively, our study sheds light on the critical function of CDYL in the maintenance of cortical neural stem cell fate commitment during human corticogenesis through the inhibition of NNAT expression.
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Project description:This is the model described in: Feedback between p21 and reactive oxygen production is necessary for cell senescence.
Passos JF, Nelson G, Wang C, Richter T, Simillion C, Proctor CJ, Miwa S, Olijslagers S, Hallinan J, Wipat A, Saretzki G, Rudolph KL, Kirkwood TB, von Zglinicki T. ;Mol Sys Biol2010;6:347. Epub 2010 Feb 16. PMID:20160708 doi:10.1038/msb.2010.5;
Abstract:
Cellular senescence--the permanent arrest of cycling in normally proliferating cells such as fibroblasts--contributes both to age-related loss of mammalian tissue homeostasis and acts as a tumour suppressor mechanism. The pathways leading to establishment of senescence are proving to be more complex than was previously envisaged. Combining in-silico interactome analysis and functional target gene inhibition, stochastic modelling and live cell microscopy, we show here that there exists a dynamic feedback loop that is triggered by a DNA damage response (DDR) and, which after a delay of several days, locks the cell into an actively maintained state of 'deep' cellular senescence. The essential feature of the loop is that long-term activation of the checkpoint gene CDKN1A (p21) induces mitochondrial dysfunction and production of reactive oxygen species (ROS) through serial signalling through GADD45-MAPK14(p38MAPK)-GRB2-TGFBR2-TGFbeta. These ROS in turn replenish short-lived DNA damage foci and maintain an ongoing DDR. We show that this loop is both necessary and sufficient for the stability of growth arrest during the establishment of the senescent phenotype.
This model originates from BioModels Database: A Database of Annotated Published Models (http://www.ebi.ac.uk/biomodels/). It is copyright (c) 2005-2010 The BioModels.net Team.For more information see the terms of use.To cite BioModels Database, please use: Li C, Donizelli M, Rodriguez N, Dharuri H, Endler L, Chelliah V, Li L, He E, Henry A, Stefan MI, Snoep JL, Hucka M, Le Novère N, Laibe C (2010) BioModels Database: An enhanced, curated and annotated resource for published quantitative kinetic models. BMC Syst Biol., 4:92.
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Project description:Cellular senescence is a homeostatic program associated with tumor suppression, wound healing, and certain age related pathologies. Senescent cells display a repressive chromatin configuration thought to stably silence proliferation-promoting genes, while at the same time activate an unusual form of immune surveillance involving a secretory program referred to as the senescence-associated secretory phenotype (SASP). Here we demonstrate that senescence also involves a global remodeling of the enhancer landscape with recruitment of the chromatin reader BRD4 to newly activated super-enhancers adjacent to key SASP genes. Transcriptional profiling and functional studies indicate that BRD4 is required for the SASP and downstream paracrine signaling. Consequently, BRD4 inhibition disrupts immune cell-mediated targeting and elimination of premalignant senescent cells in vitro and in vivo. Our results identify a critical role for BRD4-bound super-enhancers in senescence immune surveillance and in the proper execution of a tumor-suppressive program.
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