Loss of USF2 promotes proliferation, migration and mitophagy in a redox-dependent manner

Franklin, Tabughang; Khoder-Agha, Fawzi; Mennerich, Daniela; Kellokumpu, Sakari; Miinalainen, Ilkka; Kietzmann, Thomas; Dimova, Elitsa Y.

doi:10.1016/j.redox.2020.101750

Cited by 21 publications

(11 citation statements)

References 41 publications

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“…We focused our experimental validation on one such modifier, the transcription factor USF2. By tracing USF2’s function in proliferation and genome-wide expression in untreated cells, we extended conclusions from studies of USF2 in tumor suppression and cell cycle regulation (Qyang et al 1999; Pawar et al 2004; Chen et al 2006; Hu et al 2020), apoptosis (Sato et al 2011) and ERK1/2 signaling (Chi et al 2020). In an acute DNA damage setting, we discovered that USF2 is required for cells to mount DNA repair and downstream DNA damage responses.…”

Section: Discussionmentioning

confidence: 62%

A natural variation-based screen in mouse cells reveals USF2 as a regulator of the DNA damage response and cellular senescence

Kang

Moore

King

et al. 2022

Preprint

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Cellular senescence is a program of cell cycle arrest, apoptosis resistance, and cytokine release induced by stress exposure in mammalian cells. Landmark studies in laboratory mice have characterized a number of master senescence regulators, including p16INK4a, p21, NF-kB, p53, and C/EBPβ. To discover other molecular players in senescence, we developed a screening approach to harness the evolutionary divergence between mouse species. We found that primary cells from the Mediterranean mouse Mus spretus, when treated with DNA damage to induce senescence, produced less cytokine and had less-active lysosomes than cells from laboratory M. musculus. We used allele-specific expression profiling to catalog senescence-dependent cis-regulatory variation between the species at thousands of genes. We then tested for correlation between these expression changes and interspecies sequence variants in the binding sites of transcription factors. Among the emergent candidate senescence regulators, we chose a little-studied cell cycle factor, USF2, for molecular validation. In acute irradiation experiments, cells lacking USF2 exhibited compromised DNA damage repair and response.Longer-term senescent cultures without USF2 mounted an exaggerated senescence regulatory program—shutting down cell cycle and DNA repair pathways, and turning up cytokine expression, more avidly than wild-type. We interpret these findings under a model of pro-repair, anti-senescence regulatory function by USF2. Our study affords new insights into the mechanisms by which cells commit to senescence, and serves as a validated proof of concept for natural variation-based regulator screens.

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Section: Discussionmentioning

confidence: 62%

A natural variation-based screen in mouse cells reveals USF2 as a regulator of the DNA damage response and cellular senescence

Kang

Moore

King

et al. 2022

Preprint

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“…The upstream stimulatory factors (USFs) USF1 and USF2 all belong to the helix-loop-helix leucine zipper transcription factor family and function as homodimers or heterodimers by binding to the e-box of the target DNA core sequence (5′-CANNTG-3′) [ 30 , 31 ]. USFs play an important role in stress, the immune response, energy metabolism, and cell development [ 32 – 34 ]. The role of USF2 seems to be more critical than that of USF1 [ 35 , 36 ].…”

Section: Discussionmentioning

confidence: 99%

Identification of KLF6/PSGs and NPY-Related USF2/CEACAM Transcriptional Regulatory Networks via Spinal Cord Bulk and Single-Cell RNA-Seq Analysis

2021

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Background. To further understand the development of the spinal cord, an exploration of the patterns and transcriptional features of spinal cord development in newborn mice at the cellular transcriptome level was carried out. Methods. The mouse single-cell sequencing (scRNA-seq) dataset was downloaded from the GSE108788 dataset. Single-cell RNA-Seq (scRNA-Seq) was conducted on cervical and lumbar spinal V2a interneurons from 2 P0 neonates. Single-cell analysis using the Seurat package was completed, and marker mRNAs were identified for each cluster. Then, pseudotemporal analysis was used to analyze the transcription changes of marker mRNAs in different clusters over time. Finally, the functions of these marker mRNAs were assessed by enrichment analysis and protein-protein interaction (PPI) networks. A transcriptional regulatory network was then constructed using the TRRUST dataset. Results. A total of 949 cells were screened. Single-cell analysis was conducted based on marker mRNAs of each cluster, which revealed the heterogeneity of neonatal mouse spinal cord neuronal cells. Functional analysis of pseudotemporal trajectory-related marker mRNAs suggested that pregnancy-specific glycoproteins (PSGs) and carcinoembryonic antigen cell adhesion molecules (CEACAMs) were the core mRNAs in cluster 3. GSVA analysis then demonstrated that the different clusters had differences in pathway activity. By constructing a transcriptional regulatory network, USF2 was identified to be a transcriptional regulator of CEACAM1 and CEACAM5, while KLF6 was identified to be a transcriptional regulator of PSG3 and PSG5. This conclusion was then validated using the Genotype-Tissue Expression (GTEx) spinal cord transcriptome dataset. Conclusions. This study completed an integrated analysis of a single-cell dataset with the utilization of marker mRNAs. USF2/CEACAM1&5 and KLF6/PSG3&5 transcriptional regulatory networks were identified by spinal cord single-cell analysis.

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“…In addition to ROS, transcription factors can affect pyroptosis by regulating its associated molecules. For example, upstream stimulatory factor 2 (USF2), which is a member of the basic helix-loophelix-leucine zipper transcription factor family, can regulate a variety of cellular processes (Sirito et al, 1992;Chi et al, 2020). In SAKI, Sun et al found that the knockdown of USF2 led to the inhibition of the TGF-b/suppressor of mothers against d e c a p e n t a p l e g i c ( S m a d ) 3 s i g n a l i n g p a t h w a y b y downregulating the expression of thrombospondin1 (THBS1), thereby reducing pyroptosis and improving renal injury (Sun et al, 2022).…”

Section: Regulation Of Pyroptosis By Transcription Factorsmentioning

confidence: 99%

Molecular mechanisms and functions of pyroptosis in sepsis and sepsis-associated organ dysfunction

Wen

Liu

Tong

et al. 2022

Front. Cell. Infect. Microbiol.

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Sepsis, a life-threatening organ dysfunction caused by a dysregulated host response to infection, is a leading cause of death in intensive care units. The development of sepsis-associated organ dysfunction (SAOD) poses a threat to the survival of patients with sepsis. Unfortunately, the pathogenesis of sepsis and SAOD is complicated, multifactorial, and has not been completely clarified. Recently, numerous studies have demonstrated that pyroptosis, which is characterized by inflammasome and caspase activation and cell membrane pore formation, is involved in sepsis. Unlike apoptosis, pyroptosis is a pro-inflammatory form of programmed cell death that participates in the regulation of immunity and inflammation. Related studies have shown that in sepsis, moderate pyroptosis promotes the clearance of pathogens, whereas the excessive activation of pyroptosis leads to host immune response disorders and SAOD. Additionally, transcription factors, non-coding RNAs, epigenetic modifications and post-translational modifications can directly or indirectly regulate pyroptosis-related molecules. Pyroptosis also interacts with autophagy, apoptosis, NETosis, and necroptosis. This review summarizes the roles and regulatory mechanisms of pyroptosis in sepsis and SAOD. As our understanding of the functions of pyroptosis improves, the development of new diagnostic biomarkers and targeted therapies associated with pyroptosis to improve clinical outcomes appears promising in the future.

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Loss of USF2 promotes proliferation, migration and mitophagy in a redox-dependent manner

Cited by 21 publications

References 41 publications

A natural variation-based screen in mouse cells reveals USF2 as a regulator of the DNA damage response and cellular senescence

A natural variation-based screen in mouse cells reveals USF2 as a regulator of the DNA damage response and cellular senescence

Identification of KLF6/PSGs and NPY-Related USF2/CEACAM Transcriptional Regulatory Networks via Spinal Cord Bulk and Single-Cell RNA-Seq Analysis

Molecular mechanisms and functions of pyroptosis in sepsis and sepsis-associated organ dysfunction

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