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Qi Chen Lab - University of Nevada, Reno School of Medicine

Dr. Qi Chen is a reproductive & developmental biologist at University of Nevada, Reno School of Medicine.We study sperm RNAs and their roles in mediating intergenerational and transgenerational epigenetic inheritance. We are also interested in studying the molecular mechanisms of Symmetry-breaking in mammalian early embryo.Our recent works focus on sperm tsRNAs (tRNA-derived small RNAs) and its role in epigenetic memory, showing that sperm tsRNAs act as a type of paternal epigetic factor that contribute to intergenerational inheritance of an acquired metabolic disorder.Research from his lab add to the growing body of inheritable factors beyond DNA sequences, leading to a resurrected lamarckism, that inheritance of acquired characteristics during environmental exposure do happens under epigenetic regulations.Website: http://qichen-lab.info/

qI CHEN LAB

Blastomere equality

Qi Chen lab: Research

1. Discovery of sperm tsRNAs as information carrier for acquired epigenetic inheritance. The search for sperm epigenetic factors that could transmit acquired phenotypes is the key question for the rapidly developing field of transgenerational epigenetic inheritance. Our group was the first to report the existence of abundant tsRNAs in mammalian sperm (Cell Res, 2012), and also provided the first functional evidence that sperm tsRNAs contribute to the intergenerational transmission of acquired metabolic disorder from father to offspring (Science, 2015). Our findings thus strongly indicate that sperm tsRNAs is a type of paternal information carrier that mediate intergenerational epigenetic inheritance. Importantly, we also found that RNA modifications in sperm tsRNAs are important for their stabilization after entering the oocytes, and are essential for tsRNAs’ function as epigenetic information carrier (Science, 2015). We are also one of the first groups that identified the abundant and conservative existence of tsRNAs in the serum of a wide range of vertebrates, that serum tsRNAs are sensitive to pathological conditions in mice, monkey and human beings, and that RNA modifications in tsRNAs contribute to their stabilization in the serum (J Mol Cell Biol, 2014). These discoveries raise the open question about the working mechanisms of tsRNAs, as well as their RNA modifications and responsible enzymes, in mediating such epigenetic inheritance, which opened future avenues for intensive investigations.2. Deciphering molecular mechanisms for intrauterine embryo distribution and embryo orientation. Mammalian blastocysts show remarkably consistent distribution pattern and embryo orientation with respect to the uterine structure. These long-time evolved patterns bear great biological significance and the disruption of which would lead to adverse effects on pregnancies (Mol Aspect Med, 2013). The molecular mechanisms responsible for these traits involve an intricate interplay between the embryo and uteri, which are the continuous interests of both reproductive and developmental biologists. We recently provided strong evidence demonstrating the importance of myometrium peristalsis and fluid dynamics in intrauterine embryo localization and implantation, including defining the role of sympathetic activation through β2-Adrenoceptor (β2-AR) signaling for intrauterine embryo location and its profound link with ongoing pregnancy (J Biol Chem, 2011); and defining the role of Aquaporin-mediated excessive intrauterine fluid as a major contributor in hyper-estrogen induced aberrant embryo implantation (Cell Res, 2015). Both discoveries shed new light on the biomechanical and molecular mechanisms that govern intrauterine embryo localization, as well as the profound effects on successful pregnancy. We also provided the first genetic evidence that normal mammalian embryo-uterine orientation and subsequent embryo development require stage-specific uterine RBPJ signaling (Cell Res, 2014), substantiating the concept that normal mammalian embryo-uterine orientation requires proper guidance from developmentally controlled uterine signaling.3. Discovery of a water channel protein essential for rapid sperm osmoadaptation. In the journey from the male to female reproductive tract, mammalian sperm experience a natural osmotic decrease (e.g., in mouse, from ~415 mOsm in the cauda epididymis to ~310 mOsm in the uterine cavity). On one hand, the hypotonic stress upon is beneficial for mouse sperm motility “start-up” (evolutionary trait from fish sperm), but like a double-edged sword, the hypotonic stress could also cause potential harm to sperm function by inducing un-wanted cell swelling. To counteract this negative impact, mammalian sperm have acquired mechanisms to drive rapid transmembrane water movement towards efficient cell volume regulation. However, the specific sperm proteins responsible for this rapid osmoadaptation remain elusive. Using a knockout model, we discovered that Aquaporin-3 (AQP3) is an essential membrane protein for sperm regulatory volume decrease (RVD) upon physiological hypotonicity, balancing the “trade-off” between hypotonic induced sperm motility and cell swelling, thereby optimizing postcopulatory sperm behavior (Cell Res, 2011). Moreover, we found that AQP3's role in sperm osmoadaptation cannot be fully explained by considering AQPs as inert pores simply for water permeability (which is a convention view), but implicating AQP3’s role in active membrane mechanosensing (Acta Pharmacol Sin, 2011), a direction we are following with, which could potentially change the current view of aquaporin biology. 4. Developing a new model for mammalian early embryo symmetry-breaking process. In mammalian preimplantation embryo development, when the first asymmetry emerges and how it develops to direct distinct cell fates are two longstanding questions. It remains debatable whether the first bifurcation of cell fate emerges randomly at morula stage, or has been predetermined at earlier stages before morphological distinction. Combining single-cell RNA-seq ysis and mathematical modeling, we recently showed that the very first symmetry-breaking process involves both chance separation and defined transcriptional circuits (Development, 2015). This new model reconciles the previously contradictory “deterministic” versus “stochastic” views of the early mammalian embryo, creating a new framework for future detailed investigations including genetic lineage tracing and functional investigation in the early embryo context.Website: http://qichen-lab.info/

qI CHEN LAB

Hidden information in sperm small RNAs: tRNA-derived small RNA (tsRNA)

Qi Chen Lab: People

Qi Chen, M.D., Ph.DAfter I got my M.D. at Chongqing Medical University, I began my research with a project studying mouse embryo implantation with Dr. Enkui Duan at Institute of Zoology, Chinese Academy of Sciences, where I grown an interest in the molecular & biomechanical mechanisms to control intrauterine embryo localization and embryo orientation. After a twisted and exciting journey of discovery, I ended up to study water channels (aquaporins, AQPs) in reproductive system, discovering AQP3's role in sperm osmoadaptation, which turned out to be my Ph.D thesis. After the experience of working on sperm, I moved on to study the sperm-borne information (particularly those aside from DNA), and found a novel cl of tRNA-derived small RNAs (tsRNAs), also known as tRFs (tRNA fragments) that are highly enriched in sperm. The function of sperm tsRNAs as paternal epigenetic information carrier and related regulation mechanisms are the focuses of my current research. I also developed a keen interest on the origin (molecular and cellular) of early mammalian embryo symmetry-breaking before blastocyst formation, for which we are now utilizing the power of single-cell technology and mathematical modeling to study with.Website: http://qichen-lab.info/

qI CHEN LAB

Qi Chen Lab: Publications

1. Discovery of sperm tsRNAs as information carrier for acquired epigenetic inheritance. The search for sperm epigenetic factors that could transmit acquired phenotypes is the key question for the rapidly developing field of transgenerational epigenetic inheritance. Our group was the first to report the existence of abundant tsRNAs in mammalian sperm (Cell Res, 2012), and also provided the first functional evidence that sperm tsRNAs contribute to the intergenerational transmission of acquired metabolic disorder from father to offspring (Science, 2015). Our findings thus strongly indicate that sperm tsRNAs is a type of paternal information carrier that mediate intergenerational epigenetic inheritance. Importantly, we also found that RNA modifications in sperm tsRNAs are important for their stabilization after entering the oocytes, and are essential for tsRNAs’ function as epigenetic information carrier (Science, 2015). We are also one of the first groups that identified the abundant and conservative existence of tsRNAs in the serum of a wide range of vertebrates, that serum tsRNAs are sensitive to pathological conditions in mice, monkey and human beings, and that RNA modifications in tsRNAs contribute to their stabilization in the serum (J Mol Cell Biol, 2014). These discoveries raise the open question about the working mechanisms of tsRNAs, as well as their RNA modifications and responsible enzymes, in mediating such epigenetic inheritance, which opened future avenues for intensive investigations.2. Deciphering molecular mechanisms for intrauterine embryo distribution and embryo orientation. Mammalian blastocysts show remarkably consistent distribution pattern and embryo orientation with respect to the uterine structure. These long-time evolved patterns bear great biological significance and the disruption of which would lead to adverse effects on pregnancies (Mol Aspect Med, 2013). The molecular mechanisms responsible for these traits involve an intricate interplay between the embryo and uteri, which are the continuous interests of both reproductive and developmental biologists. We recently provided strong evidence demonstrating the importance of myometrium peristalsis and fluid dynamics in intrauterine embryo localization and implantation, including defining the role of sympathetic activation through β2-Adrenoceptor (β2-AR) signaling for intrauterine embryo location and its profound link with ongoing pregnancy (J Biol Chem, 2011); and defining the role of Aquaporin-mediated excessive intrauterine fluid as a major contributor in hyper-estrogen induced aberrant embryo implantation (Cell Res, 2015). Both discoveries shed new light on the biomechanical and molecular mechanisms that govern intrauterine embryo localization, as well as the profound effects on successful pregnancy. We also provided the first genetic evidence that normal mammalian embryo-uterine orientation and subsequent embryo development require stage-specific uterine RBPJ signaling (Cell Res, 2014), substantiating the concept that normal mammalian embryo-uterine orientation requires proper guidance from developmentally controlled uterine signaling.3. Discovery of a water channel protein essential for rapid sperm osmoadaptation. In the journey from the male to female reproductive tract, mammalian sperm experience a natural osmotic decrease (e.g., in mouse, from ~415 mOsm in the cauda epididymis to ~310 mOsm in the uterine cavity). On one hand, the hypotonic stress upon is beneficial for mouse sperm motility “start-up” (evolutionary trait from fish sperm), but like a double-edged sword, the hypotonic stress could also cause potential harm to sperm function by inducing un-wanted cell swelling. To counteract this negative impact, mammalian sperm have acquired mechanisms to drive rapid transmembrane water movement towards efficient cell volume regulation. However, the specific sperm proteins responsible for this rapid osmoadaptation remain elusive. Using a knockout model, we discovered that Aquaporin-3 (AQP3) is an essential membrane protein for sperm regulatory volume decrease (RVD) upon physiological hypotonicity, balancing the “trade-off” between hypotonic induced sperm motility and cell swelling, thereby optimizing postcopulatory sperm behavior (Cell Res, 2011). Moreover, we found that AQP3's role in sperm osmoadaptation cannot be fully explained by considering AQPs as inert pores simply for water permeability (which is a convention view), but implicating AQP3’s role in active membrane mechanosensing (Acta Pharmacol Sin, 2011), a direction we are following with, which could potentially change the current view of aquaporin biology. 4. Developing a new model for mammalian early embryo symmetry-breaking process. In mammalian preimplantation embryo development, when the first asymmetry emerges and how it develops to direct distinct cell fates are two longstanding questions. It remains debatable whether the first bifurcation of cell fate emerges randomly at morula stage, or has been predetermined at earlier stages before morphological distinction. Combining single-cell RNA-seq ysis and mathematical modeling, we recently showed that the very first symmetry-breaking process involves both chance separation and defined transcriptional circuits (Development, 2015). This new model reconciles the previously contradictory “deterministic” versus “stochastic” views of the early mammalian embryo, creating a new framework for future detailed investigations including genetic lineage tracing and functional investigation in the early embryo context.Website: http://qichen-lab.info/

qI CHEN LAB

Qi Chen Lab News

Dr. Qi Chen is a reproductive & developmental biologist at University of Nevada School of Medicine.We study sperm samll RNAs and epigenetic inheritance, paticularly sperm non-coding RNAs in acquired epigenetic memory, and transgenerational epigenetic inheritance. We are also interested in studying the molecular mechanisms of Symmetry-breaking in mammalian early embryo.Our recent works focus on sperm tsRNAs (tRNA derived small RNAs) and its role in epigenetic memory, showing that sperm tsRNAs act as a type of paternal epigetic factor that contribute to intergenerational inheritance of an acquired metabolic disorder.Research from his lab add to the growing body of inheritable factors beyond DNA sequences, leading to a resurrected lamarckism, that inheritance of acquired characteristics during environmental exposure do happens under epigenetic regulations.Website: http://qichen-lab.info/

qI CHEN LAB