Targeting Runt-Related Transcription Factor 1 Prevents Pulmonary Fibrosis and Reduces Expression of Severe Acute Respiratory Syndrome Coronavirus 2 Host Mediators

O’Hare, Michael; Amarnani, Dhanesh; Whitmore, Hannah; An, Miranda; Mariño, Claudia; Ramos, Leslie; Delgado-Tirado, Santiago; Hu, Xinyao; Chmielewska, Natalia; Chandrahas, Anita; Fitzek, Antonia; Heinrich, Fabian; Steurer, Stefan; Ondruschka, Benjamin; Glatzel, Markus; Krasemann, Susanne; Sepulveda‐Falla, Diego; Lagares, David; Pedron, Julien; Bushweller, John H.; Liu, Paul; Arboleda‐Velásquez, Joseph F.; Kim, Leo A.

doi:10.1016/j.ajpath.2021.04.006

Cited by 18 publications

(22 citation statements)

References 60 publications

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“…De novo transcription factor (TF) motif enrichment analysis of the genomic loci exhibiting increased accessibility at 14 dpi implicated candidate transcription factors Fosl1, Runx1, and Egr2, consistent with prior reports implicating these factors in tissue fibrosis (Fig. 2d) (Fang et al , 2011; Wernig et al , 2017; Koth et al , 2020; O’Hare et al , 2021). Motif analysis in the genomic regions exhibiting decreased accessibility at 14 dpi implicated loss of candidate transcription factors Twist2, Nfix, and Creb5 (Fig.…”

Section: Resultssupporting

confidence: 88%

“…CC-BY-ND 4.0 International license available under a (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. Wernig et al, 2017;Koth et al, 2020;O'Hare et al, 2021). Motif analysis in the genomic regions exhibiting decreased accessibility at 14 dpi implicated loss of candidate transcription factors Twist2, Nfix, and Creb5 (Fig.…”

Section: Atacseq Reveals Dynamic and Largely Reversible Chromatin Alt...mentioning

confidence: 95%

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Lung injury epigenetically primes mesenchyme for amplified activation upon re-injury

Jones

Caporarello

Meridew

et al. 2022

Preprint

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The lungs have a remarkable capacity to repair. However, repetitive injury can lead to progressive fibrosis and end-stage organ failure. Whether tissue-resident mesenchymal cell populations retain epigenetic memory of prior injuries that contribute to this pathological process is unknown. Here we used a genetic lineage labeling approach to mark the lung mesenchyme prior to injury, then performed multi-modal analyses on isolated lung mesenchyme during the initiation, progression and resolution of the fibrotic response. Our results demonstrate the remarkable epigenetic and transcriptional plasticity of the lung mesenchyme during fibrogenic activation and de-activation. Despite this plasticity, we also find that the lung mesenchyme retains specific epigenetic traits (memory) of prior activation, resulting in amplified induction of a fibrogenic program upon re-injury. We identify Runx1 as a critical driver of both fibrogenic activation and epigenetic memory. Comparison of fresh isolated and cultured lung mesenchyme demonstrates that Runx1 is spontaneously activated in standard culture conditions, previously masking these roles of Runx1. Genetic and pharmacological targeting of Runx1 dampens fibrogenic mesenchymal cell activation in cell and tissue models, confirming its functional importance. Finally, publicly available scRNAseq data reveal selective expression of Runx1 in the fibrogenic cell subpopulations that emerge in mouse and human fibrotic lung tissue. Collectively, our findings implicate Runx1 in both the initiation and memory of fibrogenic mesenchymal cell activation that together prime amplified mesenchymal cell responses upon repeated injury.

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Section: Resultssupporting

confidence: 88%

Section: Atacseq Reveals Dynamic and Largely Reversible Chromatin Alt...mentioning

confidence: 95%

Lung injury epigenetically primes mesenchyme for amplified activation upon re-injury

Jones

Caporarello

Meridew

et al. 2022

Preprint

View full text Add to dashboard Cite

show abstract

“…Pulmonary fibrosis is a common response to multiple pathologies [87][88][89]. Fibrosis is also related to aging [90], lung infection processes [91], and chemical intoxications [92][93][94]. Our study also showed that Cd caused advanced pulmonary fibrosis, capillary fragility, and numerous fused alveoli when casein was the protein source in the diet (Figure 1A).…”

Section: Soy and The Respiratory Systemsupporting

confidence: 53%

Soybean Seed Compounds as Natural Health Protectors

Boldrini¹,

Molinero²,

Chaca³

et al. 2022

Legumes Research - Volume 2

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Glycine max (L) Merrill, better known as soy or soybean, is a legume of asian origin considered an excellent biotype, given the fact that it contains almost everything the human being needs for the diet. Its cultivation worldwide is one of the most important, and soy itself and its derivatives are highly on demand. The health effects of soy derived foods have been investigated for more than 25 years, and some of them remain controversial. On the other hand, we wondered if soy could be used to ameliorate the toxic effects of heavy metals. Therefore, in this chapter we review general characteristics of soy as well as its nutritional potential, and we compiled the newest information about the health effects of soy. In order to test our hypothesis, we developed a model of animals exposed to cadmium, and we gave them a soy based diet, comparing it with a casein-based diet as control. This allowed us to collect information about its effect on the respiratory and nervous system. Among the results of this review, we show that it reduces the cholesterol level and obesity while also having antidiabetic effects. We enumerate the benefits of soy-based diets on the respiratory system, such as protection against lung cancer and radiotherapy, better lung function in asthma patients and protection against cadmium intoxication. In the cardiovascular system it reduces the risk of coronary heart disease, improves blood pressure, glycemic control, and inflammation while it reduces not all but some of the alterations induced by cadmium exposure on the aorta and heart. It apparently promotes neurogenesis, improves cognitive functions, and reduces the oxidative stress and apoptosis induced by cadmium exposure in the cerebellum. Taken all together, this information let us conclude that soy consumption would exhibit numerous benefits for human health, although future studies should try to elucidate the best outcome considering variables such as gender, age, treatment duration and dosage of soy products consumption in the diet.

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“…Hyper activation of the NFκB pathway involves the survival, activation, and differentiation of innate immune cells, inflammatory T cells and has been implicated in the pathogenesis of severe/critical COVID-19 patients [77]. Other TFs like NFE2L2/NRF2, known to regulate the expression of antioxidant proteins [78], KLF2, a master regulator of vascular homeostasis [79], HIF1A, known to regulate genes in response to hypoxia [80], MYC [81], RUNX1 [82], FOXC1, GATA2, YY1, E2F1, NFIC, FOXL1 and SRF [83,84] have been implicated in COVID-19.…”

Section: Transcription Factors In Sars-cov-2 Infectionmentioning

confidence: 99%

Co-Regulation of Protein Coding Genes by Transcription Factor and Long Non-Coding RNA in SARS-CoV-2 Infected Cells: An In Silico Analysis

Saha

Laha

Chatterjee

et al. 2021

ncRNA

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Altered expression of protein coding gene (PCG) and long non-coding RNA (lncRNA) have been identified in SARS-CoV-2 infected cells and tissues from COVID-19 patients. The functional role and mechanism (s) of transcriptional regulation of deregulated genes in COVID-19 remain largely unknown. In the present communication, reanalyzing publicly available gene expression data, we observed that 66 lncRNA and 5491 PCG were deregulated in more than one experimental condition. Combining our earlier published results and using different publicly available resources, it was observed that 72 deregulated lncRNA interacted with 3228 genes/proteins. Many targets of deregulated lncRNA could also interact with SARS-CoV-2 coded proteins, modulated by IFN treatment and identified in CRISPR screening to modulate SARS-CoV-2 infection. The majority of the deregulated lncRNA and PCG were targets of at least one of the transcription factors (TFs), interferon responsive factors (IRFs), signal transducer, and activator of transcription (STATs), NFκB, MYC, and RELA/p65. Deregulated 1069 PCG was joint targets of lncRNA and TF. These joint targets are significantly enriched with pathways relevant for SARS-CoV-2 infection indicating that joint regulation of PCG could be one of the mechanisms for deregulation. Over all this manuscript showed possible involvement of lncRNA and mechanisms of deregulation of PCG in the pathogenesis of COVID-19.

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Targeting Runt-Related Transcription Factor 1 Prevents Pulmonary Fibrosis and Reduces Expression of Severe Acute Respiratory Syndrome Coronavirus 2 Host Mediators

Cited by 18 publications

References 60 publications

Lung injury epigenetically primes mesenchyme for amplified activation upon re-injury

Lung injury epigenetically primes mesenchyme for amplified activation upon re-injury

Soybean Seed Compounds as Natural Health Protectors

Co-Regulation of Protein Coding Genes by Transcription Factor and Long Non-Coding RNA in SARS-CoV-2 Infected Cells: An In Silico Analysis

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