Time Scales in Epigenetic Dynamics and Phenotypic Heterogeneity of Embryonic Stem Cells

Sasai, Masaki,Kawabata, Yudai,Makishi, Koh,Itoh, Kazuhito,Terada, Tomoki P.,Marti-Renom, Marc A. Public Library of Science 2013 PLoS computational biology Vol.9 No.12

<▼1><P>A remarkable feature of the self-renewing population of embryonic stem cells (ESCs) is their phenotypic heterogeneity: Nanog and other marker proteins of ESCs show large cell-to-cell variation in their expression level, which should significantly influence the differentiation process of individual cells. The molecular mechanism and biological implication of this heterogeneity, however, still remain elusive. We address this problem by constructing a model of the core gene-network of mouse ESCs. The model takes account of processes of binding/unbinding of transcription factors, formation/dissolution of transcription apparatus, and modification of histone code at each locus of genes in the network. These processes are hierarchically interrelated to each other forming the dynamical feedback loops. By simulating stochastic dynamics of this model, we show that the phenotypic heterogeneity of ESCs can be explained when the chromatin at the <I>Nanog</I> locus undergoes the large scale reorganization in formation/dissolution of transcription apparatus, which should have the timescale similar to the cell cycle period. With this slow transcriptional switching of <I>Nanog</I>, the simulated ESCs fluctuate among multiple transient states, which can trigger the differentiation into the lineage-specific cell states. From the simulated transitions among cell states, the epigenetic landscape underlying transitions is calculated. The slow <I>Nanog</I> switching gives rise to the wide basin of ESC states in the landscape. The bimodal Nanog distribution arising from the kinetic flow running through this ESC basin prevents transdifferentiation and promotes the definite decision of the cell fate. These results show that the distribution of timescales of the regulatory processes is decisively important to characterize the fluctuation of cells and their differentiation process. The analyses through the epigenetic landscape and the kinetic flow on the landscape should provide a guideline to engineer cell differentiation.</P></▼1><▼2><P><B>Author Summary</B></P><P>Embryonic stem cells (ESCs) can proliferate indefinitely by keeping pluripotency, i.e., the ability to differentiate into any cell-lineage. ESCs, therefore, have been the focus of intense biological and medical interests. A remarkable feature of ESCs is their phenotypic heterogeneity: ESCs show large cell-to-cell fluctuation in the expression level of Nanog, which is a key factor to maintain pluripotency. Since Nanog regulates many genes in ESCs, this fluctuation should seriously affect individual cells when they start differentiation. In this paper we analyze this phenotypic fluctuation by simulating the stochastic dynamics of gene network in ESCs. The model takes account of the mutually interrelated processes of gene regulation such as binding/unbinding of transcription factors, formation/dissolution of transcription apparatus, and histone-code modification. We show the distribution of timescales of these processes is decisively important to characterize the dynamical behavior of the gene network, and that the slow formation/dissolution of transcription apparatus at the <I>Nanog</I> locus explains the observed large fluctuation of ESCs. The epigenetic landscapes are calculated based on the stochastic simulation, and the role of the phenotypic fluctuation in the differentiation process is analyzed through the landscape picture.</P></▼2>

Innate, adaptive, and cell-autonomous immunity against Toxoplasma gondii infection

Miwa Sasai,Masahiro Yamamoto 생화학분자생물학회 2019 Experimental and molecular medicine Vol.51 No.-

Hosts have been fighting pathogens throughout the evolution of all infectious diseases. Toxoplasma gondii is one of the most common infectious agents in humans but causes only opportunistic infection in healthy individuals. Similar to antimicrobial immunity against other organisms, the immune response against T. gondii activates innate immunity and in turn induces acquired immune responses. After activation of acquired immunity, host immune cells robustly produce the proinflammatory cytokine interferon-γ (IFN-γ), which activates a set of IFN-γ-inducible proteins, including GTPases. IFN-inducible GTPases are essential for cell-autonomous immunity and are specialized for effective clearance and growth inhibition of T. gondii by accumulating in parasitophorous vacuole membranes. Recent studies suggest that the cell-autonomous immune response plays a protective role in host defense against not only T. gondii but also various intracellular bacteria. Moreover, the negative regulatory mechanisms of such strong immune responses are also important for host survival after infection. In this review, we will discuss in detail recent advances in the understanding of host defenses against T. gondii and the roles played by cell-autonomous immune responses.

Induction of allergic contact dermatitis by astigmatid mite-derived monoterpene, α-acaridial

Toshio Sasai,Yunosuke Hirano,Sayaka Maeda,Isamu Matsunaga,Atsushi Otsuka,Daisuke Morita,Ritsuo Nishida,Hideo Nakayama,Yasumasa Kuwahara,Masahiko Sugita,Naoki Mori 한국응용곤충학회 2008 한국응용곤충학회 학술대회논문집 Vol.2008 No.10

α-Acaridial [2(E)-(4-methyl-3-pentenyl)butenedial] is a novel monoterpene secreted from the house dust mites. Because of its molecular nature of a highly reactive, small lipidic compound, we addressed whether α-acaridial might function as a haptenic allergen that induced allergic contact dermatitis. Mice sensitized with α-acaridial were challenged by the same antigen on the ear skin. After 2 days, significant ear swelling with a prominent infiltration of CD4+ T lymphocytes was observed. In vitro, α-acaridial exhibited an outstanding ability to quickly interact with and chemically modify a reference protein. Virtually all cysteine residues and a sizable fraction of lysine residues were found to be selectively modified, suggesting that α-acaridial could potentially interact with any proteins. Previously, numerous mite-derived proteinaceous allergens have been associated with contact dermatitis. Our study now emphasizes that small lipidic compounds released from mites comprise a new class of mite allergens, and therefore, is of significant medical implications.

Eddy current and coupled landscapes for nonadiabatic and nonequilibrium complex system dynamics

Zhang, Kun,Sasai, Masaki,Wang, Jin National Academy of Sciences 2013 PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF Vol.110 No.37

<P>Physical and biological systems are often involved with coupled processes of different time scales. In the system with electronic and atomic motions, for example, the interplay between the atomic motion along the same energy landscape and the electronic hopping between different landscapes is critical: the system behavior largely depends on whether the intralandscape motion is slower (adiabatic) or faster (nonadiabatic) than the interlandscape hopping. For general nonequilibrium dynamics where Hamiltonian or energy function is unknown a priori, the challenge is how to extend the concepts of the intra- and interlandscape dynamics. In this paper we establish a theoretical framework for describing global nonequilibrium and nonadiabatic complex system dynamics by transforming the coupled landscapes into a single landscape but with additional dimensions. On this single landscape, dynamics is driven by gradient of the potential landscape, which is closely related to the steady-state probability distribution of the enlarged dimensions, and the probability flux, which has a curl nature. Through an example of a self-regulating gene circuit, we show that the curl flux has dramatic effects on gene regulatory dynamics. The curl flux and landscape framework developed here are easy to visualize and can be used to guide further investigation of physical and biological nonequilibrium systems.</P>

Entropic mechanism of large fluctuation in allosteric transition

Itoh, K.,Sasai, M. National Academy of Sciences 2010 PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF Vol.107 No.17

Role of Mouse and Human Autophagy Proteins in IFN-γ–Induced Cell-Autonomous Responses against <i>Toxoplasma gondii</i>

Ohshima, Jun,Lee, Youngae,Sasai, Miwa,Saitoh, Tatsuya,Su Ma, Ji,Kamiyama, Naganori,Matsuura, Yoshiharu,Pann-Ghill, Suh,Hayashi, Mikako,Ebisu, Shigeyuki,Takeda, Kiyoshi,Akira, Shizuo,Yamamoto, Masahiro The American Association of Immunologists, Inc. 2014 JOURNAL OF IMMUNOLOGY Vol.192 No.7

<P>IFN-γ mediates cellular innate immunity against an intracellular parasite, <I>Toxoplasma gondii</I>, by inducing immunity-related GTPases such as p47 IFN-γ–regulated GTPases (IRGs) and p65 guanylate-binding proteins (GBPs), which also participate in antibacterial responses via autophagy. An essential autophagy protein, Atg5, was previously shown to play a critical role in anti–<I>T. gondii</I> cell-autonomous immunity. However, the involvement of other autophagy proteins remains unknown. In this study, we show that essential autophagy proteins differentially participate in anti–<I>T. gondii</I> cellular immunity by recruiting IFN-γ–inducible GTPases. IFN-γ–induced suppression of <I>T. gondii</I> proliferation and recruitment of an IRG Irgb6 and GBPs are profoundly impaired in Atg7- or Atg16L1-deficient cells. In contrast, cells lacking other essential autophagy proteins, Atg9a and Atg14, are capable of mediating the anti–<I>T. gondii</I> response and recruiting Irgb6 and GBPs to the parasites. Although IFN-γ also stimulates anti–<I>T. gondii</I> cellular immunity in humans, whether this response requires GBPs and human autophagy proteins remains to be seen. To analyze the role of human ATG16L1 and GBPs in IFN-γ–mediated anti–<I>T. gondii</I> responses, human cells lacking ATG16L1 or GBPs were generated by the Cas9/CRISPR genome-editing technique. Although both ATG16L1 and GBPs are dispensable for IFN-γ–induced inhibition of <I>T. gondii</I> proliferation in the human cells, human ATG16L1 is also required for the recruitment of GBPs. Taken together, human ATG16L1 and mouse autophagy components Atg7 and Atg16L1, but not Atg9a and Atg14, participate in the IFN-γ–induced recruitment of the immunity-related GTPases to the intracellular pathogen.</P>

Recent Trends and Prospects in Nutritional Supplementation in Community-Dwelling Older Japanese Adults with Sarcopenia and Frailty

Hunkyung Kim,Hirouki Sasai 한국식품영양과학회 2021 한국식품영양과학회 학술대회발표집 Vol.2021 No.10

Frailty and sarcopenia among older adults have been an area of great interest in current geriatric and gerontological research. Previous studies have shown that frailty and sarcopenia are closely associated with adverse health outcomes such as functional disability, injurious falls, hospitalization, long-term care needs, morbidity, and mortality. How frailty and sarcopenia develop are still a matter of intense debate, however there have been several factors noted, such as sociodemographic factors, physical and biological factors, lifestyle and psychological factors, and chronic diseases. Currently, there are no approved medications for treating frailty and sarcopenia. A systematic review and meta-analysis summarized the effectiveness of the interventions on the management of frailty and sarcopenia. There are four treatment strategies including exercise-based intervention, nutrition-based intervention, combined exercise and nutrition intervention, and drug therapy. Among them, this time we will focus on nutritional supplementation. The nutritional intervention included supplement intake and daily dietary management. Although numerous nutrients have been tested, such as proteins, vitamin D, omega-3 fatty acids, eicosapentaenoic acid, docosahexaenoic acid, L-carnitine, and others, their effectiveness to date seems very limited and the findings from these studies have not always been consistent. In clinical practice guideline for frailty published in 2020 indicated that single nutritional interventions, such as nutritional education and nutritional supplementation, can be weakly recommended for frailty, and recommend physical exercise therapy in combination with nutritional supplementation for frailty. Many prior studies reported the effects of exercises combined with nutritional supplementations for frailty and sarcopenia. Among them, protein supplementation combined with resistance training was most commonly used in previous studies. However, the ideal nutrient components and supplement amount for frailty and sarcopenia are not yet known. Further large-scale and long-term interventions are required to confirm the most effective nutritional ingredients for the management of frailty and sarcopenia.

Examination of Generating Mechanism Concerning Father's Participation in Child-rearing

박지선,Kondo Rie,김정석,Sasai Tsukasa,Takahashi Shigesato,박천만,Nakajima Kazuo 한국보건교육건강증진학회 2009 보건교육건강증진학회지 Vol.26 No.5

This purpose of this study was to make clear the fitness to data of the causality model related to father's child-rearing participation in a double-income household. Subjects of this survey consisted of the fathers of 2,006 households that use 21 day-care centers and 4 kindergartens whose cooperation was received via the city government departments that have jurisdiction over day-care centers and kindergartens in cities A and B in prefecture I and in city C in prefecture II (city A: 499 households; city B: 1,113 households; city C: 988 households). The surveyed items consisted of the father's age, the father's educational history, the number of children, the age of the youngest child, the father's parental-role awareness, the father's daily working hours, the father's return-home time, and child-rearing participation by the father. As a result, the fit indices were found to be CFI = 0.912, GFI = 0.948, and RMSEA = 0.082. Regarding the path coefficients, the path coefficient of the pathway from the age of the youngest child to the father's parent positivity (0.08) and the path coefficient of the pathway from the father's parent positivity to child-rearing participation (0.19) were both at statistically significant levels. Also, the father's return-home time and the working hours, which were considered as disincentives exhibited a direct effect on child-rearing participation without being influenced by the father's parent positivity or parent negativity. The path coefficient of the pathway from return-home time to child-rearing participation was -0.43, and the path coefficient of the pathway from working hours to child-rearing participation was -0.13. The value of the path coefficient expressing the relationship between the return-home time and working hours was 0.80. Authors infered that it'll be the basic material to build a generation mechanism about vanity and father's child-rearing participation appropriately as a result of this research.

Fabrication of Self-Assembled Phospholipid Layer by Plasma-Assisted Method onto a Hydrophobic Polymer Surface and Its Bio-application

Shin-ichi Kondo,Yasushi Sasai,Yukinori Yamauchi,Masayuki Kuzuya 한국표면공학회 2013 한국표면공학회 학술발표회 초록집 Vol.2013 No.11

Phenotypic Relationship between Lactation Persistency and Change in Body Condition Score in First-lactation Holstein Cows

Yamazaki, Takeshi,Takeda, Hisato,Nishiura, Akiko,Sasai, Youji,Sugawara, Naoko,Togashi, Kenji Asian Australasian Association of Animal Productio 2011 Animal Bioscience Vol.24 No.5

We examined the correlations between lactation curve shape, including persistency and changes in body condition score (BCS) during early-stage (0 to 30 days in milk (DIM)), nadir-stage (31 to 90 DIM), and late-stage (91 to 240 DIM) lactation in 191 first-lactation cows. Data used were first-parity BCS records, scored twice every month after calving, and daily milk yields. Individual lactation curves were depicted by the Wilmink function. Lactation persistency was defined as the difference in estimated milk yields between 240 DIM and 60 DIM. Changes in BCSs in the early and late stages were defined as linear regression coefficients. There were no significant correlations between traits for lactation curve shape and change in BCS in early-stage lactation. Peak yield and total milk yield were negatively correlated with BCSs in nadir- and late-stage lactation and with BCS change in late-stage lactation, suggesting that cows with high lactation yields had low body reserves and health status in mid- to late lactation and had delayed recovery of body reserves. Lactation persistency was positively correlated with change in BCS in late-stage lactation, suggesting that cows with high lactation persistency tended to be healthy and to recover their body reserves well in late lactation.