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Loss of MEF2A induces replicative stress responses that trigger IFN production

ABSTRACT: Loss of MEF2A induces replicative stress responses that trigger IFN production

PROVIDER: PRJNA861309 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR24628843_1.fastq.gz	Fastqsanger.gz
	SRR24628843_2.fastq.gz	Fastqsanger.gz
	SRR24628844_1.fastq.gz	Fastqsanger.gz
	SRR24628844_2.fastq.gz	Fastqsanger.gz
	SRR24628845_1.fastq.gz	Fastqsanger.gz

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Loss of MEF2A induces replicative stress responses that trigger IFN production

Project description:Interferons (IFN) are induced by sensing of self and non-self RNA or DNA by pathogen recognition receptors. In particular, the aberrant accumulation of cytosolic nucleic acids or the accumulation of DNA lesions has the potential to activate the STING pathway to induce IFNs. While aberrant self-DNA sensing can cause autoimmunity, negative regulators keep these under check. Here we report that MEF2A is a novel negative regulator of inflammation which suppresses the induction of IFNs at homeostasis. We show that MEF2A deficiency results in the spontaneous induction of type I IFN and robust downstream ISG expression in a STING-dependent and cGAS-independent manner. We demonstrate that the IFN response elicited by MEF2A depletion could protect cells from cardiotropic virus infections. We found that the loss of MEF2A triggered the replicative stress response to promote a DDX41/STING-dependent induction type I IFN response. The replicative stress response is dependent on ATR kinase activity, as inhibition of ATR abrogated STING activation and type I IFN production. Thus, our study connects MEF2A with protection from maladaptive type I IFN responses due to replicative stress response across various cell types as well as links the DDX41-dependent activation of STING to the replicative stress response.

2023-10-01 | GSE209601 | GEO

MEF2A suppresses stress responses that trigger DDX41-dependent IFN production.

Project description:Cellular stress in the form of disrupted transcription, loss of organelle integrity, or damage to nucleic acids can elicit inflammatory responses by activating signaling cascades canonically tasked with controlling pathogen infections. These stressors must be kept in check to prevent unscheduled activation of interferon, which contributes to autoinflammation. This study examines the role of the transcription factor myocyte enhancing factor 2A (MEF2A) in setting the threshold of transcriptional stress responses to prevent R-loop accumulation. Increases in R-loops lead to the induction of interferon and inflammatory responses in a DEAD-box helicase 41 (DDX41)-, cyclic GMP-AMP synthase (cGAS)-, and stimulator of interferon genes (STING)-dependent manner. The loss of MEF2A results in the activation of ATM and RAD3-related (ATR) kinase, which is also necessary for the activation of STING. This study identifies the role of MEF2A in sustaining transcriptional homeostasis and highlights the role of ATR in positively regulating R-loop-associated inflammatory responses.

| S-EPMC10652867 | biostudies-literature

The role of MEF2A in iPSC-CMs maturation

Project description:To understand the role of MEF2A in iPSC-CMs maturation, we used MEF2A-siRNA to reduce MEF2A transcription in iPSC-CMs and then examined the changes in transcription levels

2023-02-03 | GSE196655 | GEO

MEF2A interactome in striated muscle by an affinity-purification followed by LC-MS-MS

Project description:Myocyte Enhancer Factor 2 (MEF2) proteins are involved in multiple developmental, physiological, and pathological processes in vertebrates. Protein:protein interactions underlie the plethora of biological processes impacted by MEF2A, necessitating a detailed characterization of the MEF2A interactome. A nanobody based affinity-purification/mass spectrometry strategy was employed to achieve this goal. Specifically, the MEF2A protein complexes were captured from myogenic lysates using a GFP-tagged MEF2A protein immobilized with a GBP-nanobody followed by LC-MS/MS proteomic analysis to identify MEF2A interactors.

2024-02-27 | PXD050042 | Pride

Dysregulated gene expression in cardiac chambers of adult Mef2a knockout mice

Project description:In this study, we have identified MEF2A-sensitive genes in atrial and ventricular chambers of the adult heart. MEF2A is a member of the myocyte enhancer factor 2 (MEF2) family of transcription factors. MEF2 proteins are expressed in skeletal and cardiac muscle tissues and are conserved across many mammalian species, but the gene programs regulated by MEF2A in adult cardiac chambers are largely unknown. We compared gene expression profiles between WT and Mef2a knockout atria and ventricles from adult mice, and the results identified distinct and overlapping sets of genes sensitive to the loss of MEF2A in the adult heart.

2017-10-25 | GSE95364 | GEO

Dysregulated gene expression in Mef2a knockout mice subjected to cardiotoxin-induced muscle injury

2013-02-12 | GSE41871 | GEO

Genome-wide mapping of MEF2A binding sites by CUT&Tag-seq in chicken primary myoblasts

Project description:In this study, CUT&Tag-seq technology was employed to investigate MEF2A binding sites across the entire genome of chicken primary myoblasts. CUT&Tag was performed using CUT&Tag Assay Kit for Illumina Pro (TD904-1) from Vazyme. Antibody targeting MEF2A as well as IgG were used.The final DNA library on a HiSeq PE150 platform was subjected for the analyses. This study provides a wide landscape of MEF2A target genes from chicken primary myoblasts, which supports the active role of MEF2A in avian muscle development.

2023-12-05 | GSE249097 | GEO

Dysregulated gene expression in Mef2a knockout mice subjected to cardiotoxin-induced muscle injury

Project description:We identified genes expressed in mouse skeletal muscle, during the process of muscle regeneration after injury, which are dysregulated in the absence of Mef2a expression. MEF2A is a member of the evolutionarily conserved MEF2 transcription factor family which has known roles in cardiac muscle development and function, but is not well studied in skeletal muscle. We performed a comparison of gene expression profiles in wild type and MEF2A knockout tibialis anterior muscle, seven days post-injury with cardiotoxin. The results indicated that a variety of genes expressed during muscle regeneration, predominantly microRNAs in the Gtl2-Dio3 locus, are dysregulated by the loss of MEF2A expression. Skeletal muscle RNA used in the present study included the following two sample groups: (WT) pooled total RNA from tibialis anterior muscle taken from 5 wild type mice at seven days post-injury with 10uM cardiotoxin; (KO) pooled total RNA from tibialis anterior muscle taken from 5 Mef2a knockout mice at seven days post-injury with 10uM cardiotoxin. All mice were between 2-4 months of age. Both male and female mice were used.

2013-02-12 | E-GEOD-41871 | biostudies-arrayexpress

Genome-wide screens reveal that resveratrol induces replicative stress in human cells

Project description:Using genome-wide CRISPR-Cas9 screens and other cell-based assays, we show that the pro-longevity agent resveratrol and its analogue pterostilbene induce a genetic signature of replicative stress that is similar to hydroxyurea

2020-08-04 | GSE150232 | GEO

The role of MEF2A in iPSC-CMs maturation

Project description:The role of MEF2A in iPSC-CMs maturation

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