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David Vilchez,
Leah Boyer,
Margaret Lutz,
Carsten Merkwirth,
Ianessa Morantte,
Chris Tse, Brian Spencer,
Lesley Page,
Eliezer Masliah,
W Travis Berggren,
Fred H Gage,
Andrew Dillin
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David Vilchez,
Leah Boyer,
Margaret Lutz,
Carsten Merkwirth,
Ianessa Morantte,
Chris Tse, Brian Spencer,
Lesley Page,
Eliezer Masliah,
W Travis Berggren,
Fred H Gage,
Andrew Dillin
[show abstract]
[hide abstract]
ABSTRACT: Proteostasis is critical for maintaining cell function and proteome stability may play an important role in human embryonic stem cell (hESC) immortality. Notably, hESC populations exhibit a high assembly of active proteasomes, a key node of the proteostasis
Aging Cell 03/2013; · 6.26 Impact Factor
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David Vilchez,
Leah Boyer,
Ianessa Morantte,
Margaret Lutz,
Carsten Merkwirth,
Derek Joyce, Brian Spencer,
Lesley Page,
Eliezer Masliah,
W Travis Berggren,
Fred H Gage,
Andrew Dillin
[show abstract]
[hide abstract]
ABSTRACT: Embryonic stem cells can replicate continuously in the absence of senescence and, therefore, are immortal in culture. Although genome stability is essential for the survival of stem cells, proteome stability may have an equally important role in stem-cell identity and function. Furthermore, with the asymmetric divisions invoked by stem cells, the passage of damaged proteins to daughter cells could potentially destroy the resulting lineage of cells. Therefore, a firm understanding of how stem cells maintain their proteome is of central importance. Here we show that human embryonic stem cells (hESCs) exhibit high proteasome activity that is correlated with increased levels of the 19S proteasome subunit PSMD11 (known as RPN-6 in Caenorhabditis elegans) and a corresponding increased assembly of the 26S/30S proteasome. Ectopic expression of PSMD11 is sufficient to increase proteasome assembly and activity. FOXO4, an insulin/insulin-like growth factor-I (IGF-I) responsive transcription factor associated with long lifespan in invertebrates, regulates proteasome activity by modulating the expression of PSMD11 in hESCs. Proteasome inhibition in hESCs affects the expression of pluripotency markers and the levels of specific markers of the distinct germ layers. Our results suggest a new regulation of proteostasis in hESCs that links longevity and stress resistance in invertebrates to hESC function and identity.
Nature 09/2012; 489(7415):304-8. · 36.28 Impact Factor
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Neng-Yu Lin,
Christian Beyer,
Andreas Gießl,
Trayana Kireva,
Carina Scholtysek,
Stefan Uderhardt,
Luis Enrique Munoz,
Clara Dees,
Alfiya Distler,
Stefan Wirtz,
Gerhard Krönke, Brian Spencer,
Oliver Distler,
Georg Schett,
Jörg H W Distler
[show abstract]
[hide abstract]
ABSTRACT: OBJECTIVES: Autophagy is a homeostatic process to recycle dispensable and damaged cell organelles. Dysregulation of autophagic pathways has recently been implicated in the pathogenesis of various diseases. Here, we investigated the role of autophagy during joint destruction in arthritis. METHODS: Autophagy in osteoclasts was analysed in vitro and ex vivo by transmission electron microscopy, Western blotting and immunohistochemistry for Beclin1 and Atg7. Small molecule inhibitors, LysMCre-mediated knockout of Atg7 and lentiviral overexpression of Beclin1 were used to modulate autophagy in vitro and in vivo. Osteoclast differentiation markers were quantified by real-time PCR. The extent of bone and cartilage destruction was analysed in human tumour necrosis factor α transgenic (hTNFα tg) mice after adoptive transfer with myeloid specific Atg7-deficient bone marrow. RESULTS: Autophagy was activated in osteoclasts of human rheumatoid arthritis (RA) showing increased expression of Beclin1 and Atg7. TNFα potently induced the expression of autophagy-related genes and activated autophagy in vitro and in vivo. Activation of autophagy by overexpression of Beclin1-induced osteoclastogenesis and enhanced the resorptive capacity of cultured osteoclasts, whereas pharmacologic or genetic inactivation of autophagy prevented osteoclast differentiation. Arthritic hTNFα tg mice transplanted with Atg7(fl/fl)×LysMCre(+) bone marrow cells (BMC) showed reduced numbers of osteoclasts and were protected from TNFα-induced bone erosion, proteoglycan loss and chondrocyte death. CONCLUSIONS: These findings demonstrate that autophagy is activated in RA in a TNFα-dependent manner and regulates osteoclast differentiation and bone resorption. We thus provide evidence for a central role of autophagy in joint destruction in RA.
Annals of the rheumatic diseases 09/2012; · 8.11 Impact Factor
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[show abstract]
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ABSTRACT: Forkhead box protein p1 (Foxp1), a transcription factor showing highly enriched expression in the striatum, has been implicated in central nervous system (CNS) development, but its role in the mature brain is unknown. In order to ascertain functional roles for Foxp1 in the CNS, we have identified gene targets for Foxp1 both in vitro and in vivo using genome-wide expression microarrays and chromatin-immunoprecipitation followed by high-throughput sequencing (ChIP-seq) assays. We found that mouse Foxp1 overexpression in striatal cells elicited expression changes of genes related to immune signaling, transcriptional regulation and a manually curated Huntington's disease (HD)-signaling pathway. Similar results were found when the gene expression data set was integrated with Foxp1-binding data determined from ChIP-seq analysis. In vivo lentiviral-mediated overexpression of human FOXP1 in the context of mutant huntingtin (Htt) protein resulted in a robust downregulation of glial cell-associated, immune genes, including those encoding a variety of cytokines and chemokines. Furthermore, Foxp1-induced expression changes were significantly negatively correlated with those changes elicited by mutant Htt protein in several different HD mouse models, and most significantly in post-mortem caudate from human HD subjects. We finally show that Foxp1 interacts with mutant Htt protein in mouse brain and is present in nuclear Htt aggregates in the striatum of R6/1 transgenic mice. These findings implicate Foxp1 as a key repressor of immune signaling in the CNS and suggest that the loss of Foxp1-mediated gene regulation in HD contributes to the immune dysfunction in this disease. We further suggest that Foxp1-regulated pathways might be important mediators of neuronal-glial cell communication.
Human Molecular Genetics 04/2012; 21(14):3097-111. · 7.64 Impact Factor
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Robert H Waterston,
Kerstin Lindblad-Toh,
Ewan Birney,
Jane Rogers,
Josep F Abril,
Pankaj Agarwal,
Richa Agarwala,
Rachel Ainscough,
Marina Alexandersson,
Peter An, [......],
Sophie Williams,
Richard K Wilson,
Eitan Winter,
Kim C Worley,
Dudley Wyman,
Shan Yang,
Shiaw-Pyng Yang,
Evgeny M Zdobnov,
Michael C Zody,
Eric S Lander
[show abstract]
[hide abstract]
ABSTRACT: The sequence of the mouse genome is a key informational tool for understanding the contents of the human genome and a key experimental tool for biomedical research. Here, we report the results of an international collaboration to produce a high-quality draft sequence of the mouse genome. We also present an initial comparative analysis of the mouse and human genomes, describing some of the insights that can be gleaned from the two sequences. We discuss topics including the analysis of the evolutionary forces shaping the size, structure and sequence of the genomes; the conservation of large-scale synteny across most of the genomes; the much lower extent of sequence orthology covering less than half of the genomes; the proportions of the genomes under selection; the number of protein-coding genes; the expansion of gene families related to reproduction and immunity; the evolution of proteins; and the identification of intraspecies polymorphism.
Nature 01/2003; 420(6915):520-62. · 36.28 Impact Factor
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Asif T. Chinwalla,
Lisa L. Cook,
Kimberly D. Delehaunty,
Ginger A. Fewell,
Lucinda A. Fulton,
Robert S. Fulton,
Tina A. Graves,
LaDeana W. Hillier,
Elaine R. Mardis,
John D. McPherson, [......],
Susan Lucas,
Bin Ma,
W. Richard McCombie,
Michael Morgan,
Pavel Pevzner,
Glenn Tesler,
J|[ouml]|rg Schultz,
Douglas R. Smith,
John Tromp,
Kim C. Worley
[show abstract]
[hide abstract]
ABSTRACT: The sequence of the mouse genome is a key informational tool for understanding the contents of the human genome and a key experimental tool for biomedical research. Here, we report the results of an international collaboration to produce a high-quality draft sequence of the mouse genome. We also present an initial comparative analysis of the mouse and human genomes, describing some of the insights that can be gleaned from the two sequences. We discuss topics including the analysis of the evolutionary forces shaping the size, structure and sequence of the genomes; the conservation of large-scale synteny across most of the genomes; the much lower extent of sequence orthology covering less than half of the genomes; the proportions of the genomes under selection; the number of protein-coding genes; the expansion of gene families related to reproduction and immunity; the evolution of proteins; and the identification of intraspecies polymorphism.
Nature 12/2002; 420(6915):520-562. · 36.28 Impact Factor
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Robert H. Waterston,
Kerstin Lindblad-Toh,
Ewan Birney,
Jane Rogers,
Josep F. Abril,
Pankaj Agarwal,
Richa Agarwala,
Rachel Ainscough,
Marina Alexandersson,
Peter An, [......],
Sophie Williams,
Richard K. Wilson,
Eitan Winter,
Kim C. Worley,
Dudley Wyman,
Shan Yang,
Shiaw-Pyng Yang,
Evgeny M. Zdobnov,
Michael C. Zody,
Eric S. Lander
[show abstract]
[hide abstract]
ABSTRACT: The sequence of the mouse genome is a key informational tool for
understanding the contents of the human genome and a key experimental
tool for biomedical research. Here, we report the results of an
international collaboration to produce a high-quality draft sequence of
the mouse genome. We also present an initial comparative analysis of the
mouse and human genomes, describing some of the insights that can be
gleaned from the two sequences. We discuss topics including the analysis
of the evolutionary forces shaping the size, structure and sequence of
the genomes; the conservation of large-scale synteny across most of the
genomes; the much lower extent of sequence orthology covering less than
half of the genomes; the proportions of the genomes under selection; the
number of protein-coding genes; the expansion of gene families related
to reproduction and immunity; the evolution of proteins; and the
identification of intraspecies polymorphism.
Nature 11/2002; 420:520-562. · 36.28 Impact Factor
