Epigenome and lifestyle-related diseases

Introduction

　Our living environment and habits rewrite our epigenome after birth, changing our constitution and susceptibility to diseases. In recent years, it has become clear that living environment and habits affect not only the individual but alto future children. Our research group focuses on the epigenome, and aim to elucidate the mechanisms by which environmental factors regulate biological phenomena and disease onset, and to develop of new methods of preventing and treating lifestyle-related diseases.

Research on fat burning/storing constitution and epigenome

　Genetic information consists of genome and epigenome. The sequence of genomic DNA inherited from parents basically does not change, However, the epigenome is rewritten in life depending on living environment and habits. Representative examples of the epigenome include DNA methylation and the methylation and acetylation of histone proteins, which play a role in winding DNA.
　There are two types of adipocytes: white adipocytes, which store fat, and brown and beige adipocytes which burn fat (1). Brown and beige adipocytes actively metabolize sugar and fat and consume energy, so they are attracting attention not only from the perspective of obesity prevention but also from the perspective of health and beauty. Research to date has gradually revealed how living environment and habits rewrite the epigenome of adipocytes and create a constitution that is more likely to store or burn fat (Fig. 1)(2, 3). Many people may not like the cold, but in fact, continuous exposure to cold rewrites the epigenome of adipocytes, making the body more likely to burn fat (4-8). In our laboratory, we are conducting further research into the mechanisms by which living environment, eating habits, and exercise habits change the epigenome. We hope to use the knowledge gained from our research to improve metabolism and create healthy bodies that are less susceptible to disease.

Research on constitution and epigenome transmitted across generations

　In recent years, it has become clear that a father’s living environment and habits affect not only his own metabolism but also that of his future children. It has been reported that a father’s bad lifestyle habits (unbalanced diet and lack of exercise) can be transmitted to his children as a fat-storing constitution, increasing the risk of metabolic diseases（Fig. 2A） (9-12). On the other hand, it has been reported that a father’s good lifestyle habit (cold exposure or moderate exercise) can be transmitted to his children as a fat-burning constitution, decreasing the risk of metabolic diseases（Fig. 2B）（11-13）. However, there are many unknows about the mechanism by which a father’s living environment and habits are transmitted to his children as constitution. In our laboratory, we aim to clarify the mechanism of transgenerational transmission of constitution from the perspective of epigenome by analyzing DNA methylation and small RNAs in sperm. Through research into metabolic control across generations, we aim to contribute to the health of the current and future people.

Research on the interplay between epigenome and epitranscriptome

　In the central dogma of molecular biology, RNA is transcribed from DNA, and proteins are translated from RNA.
Through these processes, gene functions are expressed (Fig. 3A). DNA methylation and chemical modifications of histone proteins are the epigenome, and these epigenomes regulate the process of transcription from DNA to RNA. On the other hand, RNA also undergoes various chemical modifications, and RNA modifications are collectively called the epitranscriptome. It has been found that RNA modifications regulate gene expression by controlling the localization and stability of RNA, as well as the efficacy of translation into protein. Conventionally, the epigenome and epitranscriptome were thought to regulate gene expression at different layers. However, in recent years, it has been suggested that epigenome controls epitranscriptome, and epitranscriptome controls epigenome (14-17). In our laboratory, we would like to approach the new concept of gene expression, the “Neo-Central Dogma”, by analyzing reciprocal regulation of epigenome and epitranscriptome (Fig. 3B).

Searching for bioactive substances derived from microorganisms and chemical biology research

Introduction

　Microorganisms have greatly enriched human life. In addition to their role in food and alcohol production, one of their most notable contributions is in the field of pharmaceutical development. The development of pharmaceuticals derived from microorganisms, which began with the discovery of antibiotics such as penicillin, has led to the creation of drugs with various biological activities, including anticancer drugs, cholesterol-lowering drugs, and immunosuppressants. Our research group focuses on discovering novel bioactive substances from the diverse secondary metabolites produced by microorganisms, aiming to contribute to the development of innovative pharmaceuticals.

Research on fibrinolysis-enhancing substances

　Currently, ischemic heart disease ranks as the second leading cause of death in Japan, with cerebrovascular diseases ranking fourth, so the treatment and prevention of thrombotic disorders, which are major contributors to these diseases, are critically important worldwide. Thrombolytic agents used in the treatment of thrombotic disorders enhance the fibrinolytic system in blood vessels, leading to the degradation of formed thrombi. The fibrinolytic system is an endogenous mechanism that maintains vascular homeostasis. It involves the conversion of plasminogen, an inactive enzyme in the blood, into its active form, plasmin, through serine proteases such as tissue-type plasminogen activator (tPA) and urokinase-type plasminogen activator (uPA). Plasmin subsequently degrades fibrin, the main component of thrombi. Current thrombolytic therapies use exogenous plasminogen activators such as tPA or uPA as enzyme-based drugs in clinical settings. However, these therapies face significant challenges, including short half-life in the bloodstream, the need for high-dose administration, systemic bleeding tendencies, limitation to emergency use, and the inability for long-term application.
　In the process of searching for fibrinolytic activity-enhancing substances aimed at developing novel thrombolytic agents, we discovered malformin A1, a low-molecular-weight cyclic peptide produced by filamentous fungi (Fig 1a) (1). Analysis of mechanism of action revealed that malformin enhances plasminogen activation via uPA produced by U937 monocytic cells, a model cell line for the fibrinolysis research, at concentrations as low as a few μM (1, 2). Furthermore, it promotes fibrinolytic activity by increasing uPA gene expression via the activation of the MAPK pathway (3). These findings suggest that malformin enhances the fibrinolytic system through a mechanism of action distinct from that of existing enzyme-based drugs (Fig 1b). Currently, we are investigating the effects of malformin on vascular endothelial cells, the primary uPA-producing tissues within blood vessels.
　Additionally, in collaboration with other institutions, we are conducting further screenings for novel uPA activity-inducing substances. To date, these efforts have identified several secondary metabolites of microbial origin.

Discovery of antibacterial substances

　In recent years, the rise of drug-resistant bacteria that are unresponsive to antibiotics has become a significant concern in many countries. A notable example is the 2004 outbreak of methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant enterococci (VRE) at Akita University Hospital. Meanwhile, the development of new antibiotics has been on a declining trend. One reason for this decline is that, compared to drugs for chronic diseases, antibiotics are administered for shorter periods and therefore generate lower profits for pharmaceutical companies. Consequently, many companies have withdrawn from antibiotic development, and very few new antibiotics are being approved. Under these circumstances, there is an increasing need for academia and public institutions to develop novel antibiotics.
　To address this need, we conducted screening for new antibacterial substances using culture extracts from microorganisms, such as filamentous fungi and actinomycetes, isolated from soil in Akita Prefecture. This effort led to the discovery of etamycin A, a cyclic depsipeptide belonging to group B streptogramin antibiotics, from a culture extract of actinomycete Streptomyces sp. AUMR0230, which was isolated from river sediment in Semboku City (Fig 2) (4, 5). Etamycin A exhibited potent antibacterial activity against Gram-positive bacteria, including methicillin-resistant Staphylococcus epidermidis (MRSE), a common pathogen in hospital-acquired infections, with a minimum inhibitory concentration (MIC) of 1 μg/mL. Furthermore, when combined with griseoviridin, a group A streptogramin antibiotic, etamycin A demonstrated synergistic effects against MRSE. These findings indicate that etamycin A is an effective streptogramin antibiotic against MRSE. We are continuing to screen for antibacterial activity using microorganisms derived from Akita Prefecture's soil. So far, we have identified several microorganisms capable of producing antibacterial substances.

Discovery of brown adipose tissue-activating substances

　In recent years, the adoption of Western dietary habits has led to an increasing prevalence of obesity in Japan. Obesity is closely linked to lifestyle-related diseases such as diabetes, hypertension, and dyslipidemia, and its progression raises the risk of arteriosclerosis. Developing new therapeutic approaches for obesity has become an urgent challenge. Adipose tissue is classified into white adipose tissue, which stores energy, and brown adipose tissue, which consumes energy. Activation of brown adipose tissue, which burns energy to generate heat, is considered a promising anti-obesity strategy. We are currently establishing an evaluation system for brown adipocyte activation based on the expression levels of mitochondrial uncoupling protein 1 (UCP1), which is involved in thermogenesis in brown adipocytes (Fig 3). This evaluation system is expected to facilitate screening efforts to discover novel anti-obesity drugs that enhance the thermogenic capacity of brown adipocytes.

Cancer malignancy

Introduction

　Cancer is one of the main causes of death worldwide. Tumor tissue may become malignant in certain cases. Malignant cancer cells invade into surrounding tissues and/or acquire metastatic property, which may lead to poor prognosis of patients. Our research group aims to elucidate the mechanism of cancer malignancy and to provide potential targets for cancer therapy.

Research on the interaction between cancer and the immune system

　Activation of the immune system is essential for cancer elimination, and research using mouse tumor models has revealed that cancer malignancy is associated with immunosuppression, and that cancer cells that adapt to an immunosuppressive environment promote malignancy through various mechanisms. In our laboratory, we are studying the interaction between cancer and the immune system, and as part of this, we have discovered specific cancer cell death due to cytokine stimulation (Fig) and are currently analyzing its mechanism.

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Searching for bioactive substances derived from microorganisms and chemical biology research

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