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Aging is a complex process influenced by the environment and genotype. Numerous conserved genetic pathways and factors have been identified as key mediators of lifespan and stress responses in the nematode C. elegans. Host cell factor-1 (HCF-1) is a longevity and stress response modulator in worms. Mammalian HCF-1 is a vital transcriptional regulator which scaffolds diverse transcriptional regulatory complexes and controls gene expression. In C. elegans, HCF-1 is a repressor of the critical longevity determinant DAF-16, the homolog of mammalian FOXO transcription factors. The molecular partners of HCF-1 and the mechanisms whereby it modulates lifespan and stress responses have not been fully elucidated. My work implicated HCF-1 as a critical player in the regulatory mechanism linking DAF-16 and its coactivator SIR-2.1 in worms. Genetic analyses revealed that hcf-1 acts downstream of sir-2.1 to influence lifespan and oxidative stress response. Gene expression profiling uncovered a striking 80% overlap between the HCF-1- and SIR-2.1-regulated DAF16 target genes. Subsequent GO-term analyses of HCF-1 and SIR-2.1-coregulated DAF-16 targets suggested that HCF-1 and SIR-2.1 together regulate specific aspects of DAF-16mediated transcription important for aging and stress responses. My findings uncover a novel interaction between the key longevity determinants SIR-2.1 and HCF-1, and provide new insights into the complex regulation of DAF-16. SKN-1 transcription factor is an evolutionarily conserved protector against oxidative and xenobiotic stress and is a well-established pro-longevity factor. I demonstrated that SKN1 contributes to the enhanced oxidative stress resistance incurred by hcf-1 inactivation in a manner parallel to DAF-16. This functional interaction between HCF-1 and SKN-1 specifically occurs under excessive oxidant stress as SKN-1 is dispensable for the thermotolerance and long lifespan of hcf-1 mutants. HCF-1 represses the activation of SKN-1 to inhibit SKN-1 target genes involved in cellular detoxification pathways. To control SKN-1 activity, HCF-1 prevents nuclear accumulation of SKN-1 in response to oxidative stress. My findings reveal a new, context-specific regulatory relationship between the stress-response factors HCF-1 and SKN-1. Given that HCF-1, DAF-16, SIR-2.1, and SKN-1 are functionally conserved between C. elegans and mammals, my findings have important implications for the regulation of mammalian counterparts of these factors by HCF proteins.
The transcription factor DAF-16/FOXO is a critical longevity determinant in diverse organisms. It is the major effector of the insulin/IGF-1 signaling (IIS) cascade which is critical for regulating development, longevity, metabolism and stress resistance. However the molecular basis of how its transcriptional activity is regulated remains largely unknown. The aim of my research is to better understand the regulation of DAF-16 using C. elegans as a model system. My work reveals that the 14-3-3 protein FTT-2 is a new regulatory factor of DAF-16 in response to IIS. I found that RNAi knock down of ftt-2 specifically enhanced the IIS-mediated dauer formation. Furthermore, ftt-2 knock down caused the nuclear accumulation of DAF-16 and enhanced its transcriptional activities. In contrast to ftt-2, RNAi knock down of par-5/ftt-1, the only other 143-3 gene in C. elegans, did not show any notable effect on DAF-16 regulation, underscoring the functional specification of FTT-2 and PAR-5 despite their high sequence similarity. Using co-immunoprecipitation, I showed that FTT-2 formed a complex with DAF-16. My work indicates that FTT-2 binds DAF-16 in C. elegans and regulates DAF-16 by sequestering it in the cytoplasm. A similar mechanism of regulation of FOXO by 14-3-3 has been reported in mammalian cells, highlighting the high degree of conservation of DAF16/FOXO regulation. My work also shows that the C. elegans homolog of host cell factor 1 (HCF-1) represents a new longevity modulator and functions as a negative regulator of DAF-16. In C. elegans, hcf-1 inactivation caused a daf-16dependent lifespan extension up to 40% and heightened resistance to specific stress stimuli. HCF-1 showed ubiquitous nuclear localization and physically associated with DAF-16 in worms. Furthermore, loss of hcf-1 resulted in elevated DAF-16 recruitment to the promoters of its target genes and altered expression of a subset of DAF-16-regulated genes. We propose that HCF-1 modulates C. elegans longevity and stress response by forming a complex with DAF-16. This complex limits a fraction of DAF-16 from accessing its target gene promoters, and thereby regulating DAF-16-mediated transcription of selective target genes. As HCF-1 is highly conserved, my results have important implication for aging and FOXO regulation in mammals.
Mitochondria and Longevity, Volume 340, the latest release in the International Review of Cell and Molecular Biology series reviews and details current advances in cell and molecular biology. The IRCMB series has a worldwide readership, maintaining a high standard by publishing invited articles on important and timely topics with this release focusing on topics such as Mitochondria metabolism and aging, Mitohormesis, Mitochondrial dynamics in the aging stem cell compartment, Mitochondrial proteostasis and aging, Mitochondrial DNA mutations and aging, Mitochondrial sirtuins, NAD+, NADH and aging, Mitophagy and aging, Mitochondria, calcium transport and aging.
15 chapters on protein phosphorylation and human health written by expert scientists. Covers most important research hot points, such as Akt, AMPK and mTOR. Bridges the basic protein phosphorylation pathways with human health and diseases. Detailed and comprehensive text with excellent figure illustration.
While the first edition of the critically acclaimed and highly popular Circadian Physiologyoffered a concise but rigorous review of basic and applied research on circadian rhythms, this newest edition provides educators with the primary textbook they need to support a course on this cutting-edge topic. Maintaining the same accessible multidi
Stem cells have been gaining a lot of attention in recent years. Their unique potential to self-renew and differentiate has turned them into an attractive model for the study of basic biological questions such as cell division, replication, transcription, cell fate decisions, and more. With embryonic stem (ES) cells that can generate each cell type in the mammalian body and adult stem cells that are able to give rise to the cells within a given lineage, basic questions at different developmental stages can be addressed. Importantly, both adult and embryonic stem cells provide an excellent tool for cell therapy, making stem cell research ever more pertinent to regenerative medicine. As the title The Cell Biology of Stem Cells suggests, our book deals with multiple aspects of stem cell biology, ranging from their basic molecular characteristics to the in vivo stem cell trafficking of adult stem cells and the adult stem-cell niche, and ends with a visit to regeneration and cell fate reprogramming. In the first chapter, “Early embryonic cell fate decisions in the mouse”, Amy Ralson and Yojiro Yamanaka describe the mechanisms that support early developmental decisions in the mouse pre-implantation embryo and the current understanding of the source of the most immature stem cell types, which includes ES cells, trophoblast stem (TS) cells and extraembryonic endoderm stem (XEN) cells.
Defines the current status of research in the genetics, anatomy, and development of the nematode C. elegans, providing a detailed molecular explanation of how development is regulated and how the nervous system specifies varied aspects of behavior. Contains sections on the genome, development, neural networks and behavior, and life history and evolution. Appendices offer genetic nomenclature, a list of laboratory strain and allele designations, skeleton genetic maps, a list of characterized genes, a table of neurotransmitter assignments for specific neurons, and information on codon usage. Includes bandw photos. For researchers in worm studies, as well as the wider community of researchers in cell and molecular biology. Annotation copyrighted by Book News, Inc., Portland, OR
Molecular biology has driven a powerful reductionist, or “molecule-c- tric,” approach to biological research in the last half of the 20th century. Red- tionism is the attempt to explain complex phenomena by defining the functional properties of the individual components of the system. Bloom (1) has referred to the post-genome sequencing era as the end of “naïve reductionism. ” Red- tionist methods will continue to be an essential element of all biological research efforts, but “naïve reductionism,” the belief that reductionism alone can lead to a complete understanding of living organisms, is not tenable. Organisms are clearly much more than the sum of their parts, and the behavior of complex physiological processes cannot be understood simply by knowing how the parts work in isolation. Systems biology has emerged in the wake of genome sequencing as the s- cessor to reductionism (2–5). The “systems” of systems biology are defined over a wide span of complexity ranging from two macromolecules that interact to carry out a specific task to whole organisms. Systems biology is integrative and seeks to understand and predict the behavior or “emergent” properties of complex, multicomponent biological processes. A systems-level characteri- tion of a biological process addresses the following three main questions: (1) What are the parts of the system (i. e.
Recent studies have indicated that epigenetic processes may play a major role in both cellular and organismal aging. These epigenetic processes include not only DNA methylation and histone modifications, but also extend to many other epigenetic mediators such as the polycomb group proteins, chromosomal position effects, and noncoding RNA. The topics of this book range from fundamental changes in DNA methylation in aging to the most recent research on intervention into epigenetic modifications to modulate the aging process. The major topics of epigenetics and aging covered in this book are: 1) DNA methylation and histone modifications in aging; 2) Other epigenetic processes and aging; 3) Impact of epigenetics on aging; 4) Epigenetics of age-related diseases; 5) Epigenetic interventions and aging: and 6) Future directions in epigenetic aging research. The most studied of epigenetic processes, DNA methylation, has been associated with cellular aging and aging of organisms for many years. It is now apparent that both global and gene-specific alterations occur not only in DNA methylation during aging, but also in several histone alterations. Many epigenetic alterations can have an impact on aging processes such as stem cell aging, control of telomerase, modifications of telomeres, and epigenetic drift can impact the aging process as evident in the recent studies of aging monozygotic twins. Numerous age-related diseases are affected by epigenetic mechanisms. For example, recent studies have shown that DNA methylation is altered in Alzheimer’s disease and autoimmunity. Other prevalent diseases that have been associated with age-related epigenetic changes include cancer and diabetes. Paternal age and epigenetic changes appear to have an effect on schizophrenia and epigenetic silencing has been associated with several of the progeroid syndromes of premature aging. Moreover, the impact of dietary or drug intervention into epigenetic processes as they affect normal aging or age-related diseases is becoming increasingly feasible.