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Decidualization is a complex process involving cellular proliferation and differentiation of the endometrial stroma and is required to establish and support pregnancy. Dysregulated decidualization has been reported to be a critical cause of recurrent implantation failure (RIF). In this study, we found that Activating transcription factor 3 (ATF3) expression was significantly downregulated in the endometrium of RIF patients. Knockdown of ATF3 in human endometrium stromal cells (hESCs) hampers decidualization, while overexpression could trigger the expression of decidual marker genes, and ameliorate the decidualization of hESCs from RIF patients. Mechanistically, ATF3 promotes decidualization by upregulating FOXO1 via suppressing miR-135b expression. In addition, the endometrium of RIF patients was hyperproliferative, while overexpression of ATF3 inhibited the proliferation of hESCs through CDKN1A. These data demonstrate the critical roles of endometrial ATF3 in regulating decidualization and proliferation, and dysregulation of ATF3 in the endometrium may be a novel cause of RIF and therefore represent a potential therapeutic target for RIF.

The innate immune system is absolutely required for host defence, but, uncontrolled, it leads to inflammatory disease. This control is mediated, in part, by cytokines that are secreted by macrophages. Immune regulation is extraordinarily complex, and can be best investigated with systems approaches (that is, using computational tools to predict regulatory networks arising from global, high-throughput data sets). Here we use cluster analysis of a comprehensive set of transcriptomic data derived from Toll-like receptor (TLR)-activated macrophages to identify a prominent group of genes that appear to be regulated by activating transcription factor 3 (ATF3), a member of the CREB/ATF family of transcription factors. Network analysis predicted that ATF3 is part of a transcriptional complex that also contains members of the nuclear factor (NF)-κB family of transcription factors. Promoter analysis of the putative ATF3-regulated gene cluster demonstrated an over-representation of closely apposed ATF3 and NF-κB binding sites, which was verified by chromatin immunoprecipitation and hybridization to a DNA microarray. This cluster included important cytokines such as interleukin (IL)-6 and IL-12b. ATF3 and Rel (a component of NF-κB) were shown to bind to the regulatory regions of these genes upon macrophage activation. A kinetic model of Il6 and Il12b messenger RNA expression as a function of ATF3 and NF-κB promoter binding predicted that ATF3 is a negative regulator of Il6 and Il12b transcription, and this hypothesis was validated using Atf3 -null mice. ATF3 seems to inhibit Il6 and Il12b transcription by altering chromatin structure, thereby restricting access to transcription factors. Because ATF3 is itself induced by lipopolysaccharide, it seems to regulate TLR-stimulated inflammatory responses as part of a negative-feedback loop. You can't beat the systems Systems biology, the field that exploits data collected by genomics, proteomics and all-the-other-omics to analyse living organisms at a higher level than conventional biology, is touted as a powerful tool for dissecting complex systems. But until now it has not been particularly effective in identifying basic mechanisms in mammals. The immune response is well suited to systems analysis; mouse models are well defined and circulating cells can be purified and cultured. Gilchrist et al . have used a systems approach to kinetic modelling of TLR4-stimulated macrophages and arrive at a prediction that the transcription factor ATF3 is a negative regulator of the innate immune response, acting via chromatin remodelling. So, probably for the first time, the tools of systems biology have revealed a novel regulatory mechanism in the immune response and a possible new drug target. A three-body gravitational encounter between a binary system — with properties like that of the Pluto–Charon — and Neptune is the most likely explanation for the capture of Triton.

c-Jun dimerization protein (JDP2) and Activating Transcription Factor 3 (ATF3) are closely related basic leucine zipper proteins. Transgenic mice with cardiac expression of either JDP2 or ATF3 showed maladaptive remodeling and cardiac dysfunction. Surprisingly, JDP2 knockout (KO) did not protect the heart following transverse aortic constriction (TAC). Instead, the JDP2 KO mice performed worse than their wild type (WT) counterparts. To test whether the maladaptive cardiac remodeling observed in the JDP2 KO mice is due to ATF3, ATF3 was removed in the context of JDP2 deficiency, referred as double KO mice (dKO). Mice were challenged by TAC, and followed by detailed physiological, pathological and molecular analyses. dKO mice displayed no apparent differences from WT mice under unstressed condition, except a moderate better performance in dKO male mice. Importantly, following TAC the dKO hearts showed low fibrosis levels, reduced inflammatory and hypertrophic gene expression and a significantly preserved cardiac function as compared with their WT counterparts in both genders. Consistent with these data, removing ATF3 resumed p38 activation in the JDP2 KO mice which correlates with the beneficial cardiac function. Collectively, mice with JDP2 and ATF3 double deficiency had reduced maladaptive cardiac remodeling and lower hypertrophy following TAC. As such, the worsening of the cardiac outcome found in the JDP2 KO mice is due to the elevated ATF3 expression. Simultaneous suppression of both ATF3 and JDP2 activity is highly beneficial for cardiac function in health and disease.

Vascular smooth muscle cell (VSMC) senescence is a pivotal driver of atherosclerosis (AS), but molecular links to ageing‐related dysfunction are unclear. It is aimed to identify regulators of VSMC senescence and develop clinical interventions for ageing‐related AS. Using single‐cell RNA sequencing of human atherosclerotic carotid arteries and immunofluorescence validation, activating transcription factor 3 (ATF3) is identified as central to VSMC senescence. Mechanistic studies employ SMC‐specific ATF3 knockout mice, CUT&Tag‐seq, RNA/protein interaction assays, and m6A epitranscriptomic analyses. To bridge discovery to therapy, high‐throughput virtual screening is performed for ATF3‐targeting compounds and functionally validated hits. ATF3 deficiency in VSMCs accelerates ageing‐induced AS by promoting senescence. Multi‐omics showed ATF3 activates ATG7, triggering autophagy, while cytoplasmic ATG7 enhances ATF3 nuclear translocation, establishing a positive feedback loop. Ageing increases m6A methylation and decreases the stability of Atf3 mRNA. Terazosin (TZ) diminishes the interaction between YTH N6‐methyladenosine RNA binding protein F2 (YTHDF2) and Atf3 mRNA, helping to preserve Atf3 mRNA stability. TZ is a promising therapeutic strategy for delaying VSMC senescence and preventing AS. ATF3 protects against VSMC senescence and AS by orchestrating autophagy via a novel ATF3‐ATG7 amplification loop. Repurposing TZ to stabilize ATF3 offers a translatable approach to combat ageing‐driven cardiovascular disease. Targeting ATF3 with terazosin to against VSMC Senescence and atherosclerosis. TZ reduces the binding affinity of YTHDF2 to Atf3 mRNA, while enhancing mRNA stability. ATF3 promotes Atg7 transcription, enhancing autophagy. ATG7 binds to ATF3 in the cytoplasm, facilitating ATF3 translocation to the nucleus and establishing positive feedback. By modulating ATF3, VSMCs' senescence can be improved, which in turn inhibits atherosclerosis.

Billions of people have obesity-related metabolic syndromes such as diabetes and hyperlipidemia. Promoting the browning of white adipose tissue has been suggested as a potential strategy, but a drug still needs to be identified. Here, genetic deletion of activating transcription factor 3 ( ATF3 −/− ) in mice under a high-fat diet (HFD) resulted in obesity and insulin resistance, which was abrogated by virus-mediated ATF3 restoration. ST32da, a synthetic ATF3 inducer isolated from Salvia miltiorrhiza , promoted ATF3 expression to downregulate adipokine genes and induce adipocyte browning by suppressing the carbohydrate-responsive element-binding protein–stearoyl-CoA desaturase-1 axis. Furthermore, ST32da increased white adipose tissue browning and reduced lipogenesis in HFD-induced obese mice. The anti-obesity efficacy of oral ST32da administration was similar to that of the clinical drug orlistat. Our study identified the ATF3 inducer ST32da as a promising therapeutic drug for treating diet-induced obesity and related metabolic disorders. Ching-Feng Cheng et al. find that expression of the transcription factor ATF3 in mice provides protection from obesity and insulin resistance under a high-fat diet. They show that expression of ATF3 can be induced by ST32da, a compound derived from the Chinese sage plant, Salvia miltiorrhiza .

Activating transcription factor 3 (ATF3), which is encoded by an adaptive-response gene induced by various stimuli, plays an important role in the cardiovascular system. However, the effect of ATF3 on cardiac hypertrophy induced by a pathological stimulus has not been determined. Here, we investigated the effects of ATF3 deficiency on cardiac hypertrophy using in vitro and in vivo models. Aortic banding (AB) was performed to induce cardiac hypertrophy in mice. Cardiac hypertrophy was estimated by echocardiographic and hemodynamic measurements and by pathological and molecular analysis. ATF3 deficiency promoted cardiac hypertrophy, dysfunction and fibrosis after 4 weeks of AB compared to the wild type (WT) mice. Furthermore, enhanced activation of the MEK-ERK1/2 and JNK pathways was found in ATF3-knockout (KO) mice compared to WT mice. In vitro studies performed in cultured neonatal mouse cardiomyocytes confirmed that ATF3 deficiency promotes cardiomyocyte hypertrophy induced by angiotensin II, which was associated with the amplification of MEK-ERK1/2 and JNK signaling. Our results suggested that ATF3 plays a crucial role in the development of cardiac hypertrophy via negative regulation of the MEK-ERK1/2 and JNK pathways.

Psychological stress increases the risk of gastrointestinal (GI) tract diseases, which involve bidirectional communication of the GI and nerves systems. Acute stress leads to GI ulcers; however, the mechanism of the native cellular protection pathway, which safeguards tissue integrality and maintains GI homeostasis, remains to be investigated. In a mouse model of this study, restraint stress induced GI leakage, abnormal tight junction protein expression, and cell death of gut epithelial cells. The expression of activating transcription factor 3 (ATF3), a stress-responsive transcription factor, is upregulated in the GI tissues of stressed animals. ATF3-deficient mice displayed an exacerbated phenotype of GI injuries. These results suggested that, in response to stress, ATF3 is part of the native cellular protective pathway in the GI system, which could be a molecular target for managing psychological stress-induced GI tract diseases.

Activating transcription factor 3 (ATF3) is a negative regulator of proinflammatory cytokine expression in macrophages, and ATF3-deficient mice are more susceptible to endotoxic shock. Here, we demonstrate that ATF3 interacts with a cis-regulatory element of the IFN-γ gene in natural killer (NK) cells, and that ATF3null NK cells show increased transcription and secretion of IFN-γ. NK cell-derived IFN-γ has previously been demonstrated to be protective against murine cytomegalovirus (MCMV) infection, and we show here that ATF3null mice exhibit decreased hepatic viral load and reduced liver histopathology upon challenge with MCMV. Reconstitution of NK-deficient mice with ATF3null NK cells more effectively controlled MCMV infection than mice reconstituted with WT cells, indicating that ATF3 acts within NK cells to regulate antiviral responses.

Macrophages play an essential role in the innate immune response to infection and tissue injury. However, excessive macrophage activation may also significantly contribute to chronic inflammatory diseases. The Toll-like receptor (TLR) family are key regulators of innate immune responses in macrophages, and they are able to promote their survival and resistance against apoptosis. We, and others, have shown that the adaptive response gene, activating transcription factor 3 (ATF3), acts as a negative regulator of TLR signaling by repressing transcription of pro-inflammatory cytokines in primary mouse macrophages. Here, we describe a novel role for ATF3 as a component of TLR-mediated survival in macrophages. ATF3-deficient bone marrow macrophages show reduced survival in response to a range of TLR ligands and significantly higher apoptotic rates were observed in response to lipopolysaccharide, indicating that ATF3 is required to suppress apoptosis in macrophages. Furthermore, we show that ATF3 lies downstream of JNK signaling after TLR engagement, resulting in repression of pro-apoptotic Bak and Bax transcription.

Calcineurin versus ATF3 in cancer Squamous cell carcinoma (SCC) of the skin is a common complication of immunosuppressive treatment with calcineurin inhibitors in graft-recipient patients. Here it is shown that the intact calcineurin/NFAT signalling pathway is important for suppressing SCC development, with a key role for increased expression of the ATF3 transcription factor in tumorigenesis. Calcineurin inhibitors are the mainstay of immunosuppressive treatment for organ transplant recipients. However, treatment with these drugs commonly leads to squamous cell carcinoma (SCC) of the skin. It is shown here that an intact calcineurin/NFAT signalling pathway is important for suppressing SCC development. Inhibition of this pathway leads to increased expression of the ATF3 protein, which has a key role in tumorigenesis. Calcineurin inhibitors such as cyclosporin A (CsA) are the mainstay of immunosuppressive treatment for organ transplant recipients. Squamous cell carcinoma (SCC) of the skin is a major complication of treatment with these drugs, with a 65 to 100-fold higher risk than in the normal population 1 . By contrast, the incidence of basal cell carcinoma (BCC), the other major keratinocyte-derived tumour of the skin, of melanoma and of internal malignancies increases to a significantly lesser extent 1 . Here we report that genetic and pharmacological suppression of calcineurin/nuclear factor of activated T cells (NFAT) function promotes tumour formation in mouse skin and in xenografts, in immune compromised mice, of H-ras V12 (also known as Hras1 )-expressing primary human keratinocytes or keratinocyte-derived SCC cells. Calcineurin/NFAT inhibition counteracts p53 (also known as TRP53)-dependent cancer cell senescence, thereby increasing tumorigenic potential. ATF3, a member of the ‘enlarged’ AP-1 family, is selectively induced by calcineurin/NFAT inhibition, both under experimental conditions and in clinically occurring tumours, and increased ATF3 expression accounts for suppression of p53-dependent senescence and enhanced tumorigenic potential. Thus, intact calcineurin/NFAT signalling is critically required for p53 and senescence-associated mechanisms that protect against skin squamous cancer development.