Rudolf Jaenisch

..The two winners of the 2012 Nobel Prize in Physiology or Medicine share more than just this honor; they are both also fearless adventurers, in science and beyond...

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..However, our understanding of molecular details of the imprinting process, as well as evolutionary considerations, is rather consistent with imprinting having no intrinsic role in mammalian development...

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..This approach creates a defined system for studying reprogramming mechanisms and allows screening of genetically homogeneous cells for compounds that can replace any transcription factor required for iPS cell derivation...

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..Thus, H2AZ, together with PcG proteins, may establish specialized chromatin states in ES cells necessary for the proper execution of developmental gene expression programs...

..We demonstrate that RNA inhibition of transcription factors can facilitate reprogramming, and that treatment with DNA methyltransferase inhibitors can improve the overall efficiency of the reprogramming process...

..Our results suggest that Dnmt3a may act like a tumor-suppressor gene in lung tumor progression and may be a critical determinant of lung cancer malignancy...

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..Female mir-290-295(-/-) mice are unable to recover and are sterile, due to premature ovarian failure...

..These results indicate that PRC2 occupies a special set of developmental genes in ES cells that must be repressed to maintain pluripotency and that are poised for activation during ES cell differentiation...

..More generally, the results establish reduced representation bisulphite sequencing as a powerful technology for epigenetic profiling of cell populations relevant to developmental biology, cancer and regenerative medicine...

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..Our findings support the notion that ES cell lines derived from cloned or fertilized blastocysts have an identical therapeutic potential...

..Importantly, the virally transduced cDNAs needed to be expressed for at least 12 days in order to generate iPS cells. Our results are a step toward understanding some of the molecular events governing epigenetic reprogramming...

..Moreover, we will discuss the potential use of nuclear transfer to study the role of reversible genomic (epigenetic) modifications during tumorigenesis...

..Our results show that the biological potency and epigenetic state of in-vitro-reprogrammed induced pluripotent stem cells are indistinguishable from those of ES cells...

..This system facilitates the characterization of reprogramming and provides a tool for genetic or chemical screens to enhance reprogramming...

..Our results provide functional evidence that the differentiation and epigenetic state of the donor nucleus influences reprogramming efficiency...

..The problems associated with using retroviruses and oncogenes for reprogramming need to be resolved before iPS cells can be considered for human therapy...

..Because reprogramming factors are carried on a single polycistronic construct, the mice can be easily maintained, and the transgene can be easily transferred into other genetic backgrounds...

..These observations suggest that failure to reactivate the full spectrum of these Oct4-related genes may contribute to embryonic lethality in somatic-cell clones...

..Our results indicate that dynamic repression of developmental pathways by Polycomb complexes may be required for maintaining ES cell pluripotency and plasticity during embryonic development...

..Our findings support the notion that cancer results from the deregulation of stem cells and further suggest that the genetics of ECs will reveal genes involved in stem cell self-renewal and pluripotency...

..Our data show that the Hippo signaling pathway regulates organ size in mammals and can act on stem cell compartments, indicating a potential link between stem/progenitor cells, organ size, and cancer...

..These observations extend to differentiated cells, suggesting that transcription initiation at most genes is a general phenomenon in human cells...

..Oct4 gene ablation in these tissues revealed no abnormalities in homeostasis or regenerative capacity. We conclude that Oct4 is dispensable for both self-renewal and maintenance of somatic stem cells in the adult mammal...

..Our results indicate that postnatal, neuron-specific activation of MeCP2 as late as 2-4 weeks of age significantly prolonged the lifespan of mutant animals and delayed the onset of neurologic symptoms...

..Our findings serve as a paradigm for studying the tumorigenic effect of a given cancer genome in the context of a whole animal...

..Our results thus strongly suggest IGF-1 as a candidate for pharmacological treatment of RTT and potentially of other CNS disorders caused by delayed synapse maturation...

..Finally, downstream factors derived from the late phase, which do not include Oct4, Sox2, Klf4, c-Myc, and Nanog, can activate the pluripotency circuitry...

..Thus, iDA neurons generated from abundant somatic fibroblasts by direct lineage reprogramming hold promise for modeling neurodegenerative disease and for cell-based therapies of PD...

..Recent evidence with comparing multiple technologies suggests that expanding these datasets using different platforms would be a useful resource for examining the mechanisms underlying pluripotency regulation...

..Our findings suggest that stem cells from different genetic backgrounds can assume distinct states of pluripotency in vitro, the stability of which is regulated by endogenous genetic determinants and can be modified by exogenous factors...

..These results indicate that DNA hypomethylation plays a causal role in tumor formation, possibly by promoting chromosomal instability...

..Finally, we targeted the PITX3 gene, demonstrating that ZFNs can be used to generate reporter cells by targeting non-expressed genes in hESCs and hiPSCs...

..Our results indicate that residual transgene expression in virus-carrying hiPSCs can affect their molecular characteristics and that factor-free hiPSCs therefore represent a more suitable source of cells for modeling of human disease...

..This study provides a framework for the application of comprehensive chromatin profiling towards characterization of diverse mammalian cell populations...

..Our study provides definite proof for the direct nuclear reprogramming of terminally differentiated adult cells to pluripotency...

..These data show that certain adult progenitors remain competent to interpret key embryonic signals and support the notion that progenitor cells are a driving force in tumorigenesis...

..This strategy and the vectors described here are generally applicable to any locus in ES cells and should allow for the rapid production of mice with transgenes efficiently targeted to a defined site...

..Our results provide in vivo evidence for a functional interaction between Mecp2 and Bdnf and demonstrate the physiological significance of altered BDNF expression/signaling in RTT disease progression...

..Similarly, this cluster may mediate chemotherapeutic resistance in a neoplastic context, making it a useful clinical target...

..This concept complicates efforts to define a "generic" epigenetic state of iPSCs and ESCs and should be considered when comparing different iPS and ES cell lines...

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..These results suggest epigenetic information established during embryonic X-inactivation is functionally equivalent to the gametic imprint...

..These findings support the notion of a dual role for DNA hypomethylation in suppressing later stages of intestinal tumorigenesis, but promoting early lesions in the colon and liver through an LOH mechanism...

..In addition we have generated human induced pluripotent stem (hiPS) cell lines from human keratinocytes, demonstrating that a single polycistronic virus can reprogram human somatic cells...

..Furthermore, poised enhancer networks provide clues to unrealized developmental programs. Finally, we show that enhancers are reset during nuclear reprogramming...

..The generation of validated "naïve" human ESCs will allow the molecular dissection of a previously undefined pluripotent state in humans and may open up new opportunities for patient-specific, disease-relevant research...

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..Our results demonstrate frequent abnormal gene expression in clones, in which most expression abnormalities appear common to the NT procedure whereas others appear to reflect the particular donor nucleus...

..These data demonstrate that LOI alone can predispose cells to tumorigenesis and identify a pathway through which immortality conferred by LOI lowers the threshold for transformation...

..Near-complete bisulfite conversion and largely unbiased representation of RRBS libraries suggest that random shotgun bisulfite sequencing can be scaled to a genome-wide approach...

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..Although some variation in chromatin structure and gene expression was observed in these cell lines, these variations did not serve to distinguish ESCs from iPSCs...

..This supports the concept that transient stressors can cause permanent epigenetic changes in somatic stem cells and that these accumulate over the lifetime of an organism in analogy to DNA mutations...

..Our aim was to analyze the genetic and epigenetic consequences of folate deficiency and to investigate whether impairment of the uracil base excision repair pathway can enhance its effects...

..These data reveal how key ES cell transcription factors promote the ES cell miRNA expression program and integrate miRNAs into the regulatory circuitry controlling ES cell identity...

..Here we demonstrate that reprogrammed pluripotent cells can be isolated from genetically unmodified somatic donor cells solely based upon morphological criteria...

..These findings indicate that in the lung, Sprouty-2 plays a critical role in the regulation of oncogenic K-ras, and implicate counter-regulatory mechanisms in the pathogenesis of Ras-based disease...

..Our data suggest that Tet1 loss leading to a partial reduction in 5hmC levels does not affect pluripotency in ESCs and is compatible with embryonic and postnatal development...

..Our results implicate a role for Dnmt3a in the neuromuscular control of motor movement...

..Our results demonstrate the therapeutic potential of directly reprogrammed fibroblasts for neuronal cell replacement in the animal model...

..These findings indicate that the human blastocyst contains pre-X-inactivation cells and that this state is preserved in vitro through culture under physiological oxygen...

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..These results provide key insights into the physiologic functions of this family of microRNAs and suggest a link between the oncogenic properties of miR-17 approximately 92 and its functions during B lymphopoiesis and lung development...

..These results argue that the Xic is contained within 450 kb and that these sequences are sufficient for chromosome counting, choosing, and initiation of X inactivation...

..In conflict with the prevailing view of how choosing occurs, the element identified by the deletion plays a positive role in the choice mechanism and forces a reassessment of how X chromosome choosing is thought to occur...

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..Association of Xist RNA with chromatin is mediated by functionally redundant sequences that act cooperatively and are dispersed throughout the remainder of Xist but show little or no homology...

..These results provide new insights into the transcriptional regulation of stem cells and reveal how OCT4, SOX2, and NANOG contribute to pluripotency and self-renewal...

..These results for the first time establish a function for antisense transcription in the regulation of X inactivation...

..Mecp2 deficiency in these neurons is sufficient to cause neuronal dysfunction with symptomatic manifestation similar to Rett syndrome...

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..Our results indicate that the Xist RNA is required for female dosage compensation but plays no role in spermatogenesis...

..These studies provide a conceptual framework for understanding pluripotency and lineage-specification at the molecular level...

..Our results implicate mPRC1 in X inactivation and suggest that the regulated assembly of PcG protein complexes on the Xi contributes to this multistep process...

..Here we review recent advances in this rapidly moving field and emphasize unresolved and controversial questions...

..Here we contrast pathways known to govern pluripotency in embryonic stem cells with those in adult stem cells and critically discuss the concept of pluripotency in adult stem cells of the mammalian soma...

..This result suggests that Mecp2 deficiency leads to subtle gene expression changes in mutant brains which may be associated with the phenotypic changes observed...

..The relative ease and speed with which such transnuclear models can be obtained holds promise for the construction of other disease models...

..Indeed, gene expression analyses and extensive phenotypic characterisation of cloned animals suggest that most, if not all, clones suffer from at least subtle abnormalities...

..This short review summarizes strategies to reprogram somatic cells to a pluripotent embryonic state and discuss the implications of this technology for transplantation medicine...

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..These modifications enable generation of sufficient 'intact' transgenic clones for biological analysis with a single experiment...

..Thus, the potential for chromosome-wide gene regulation is not intrinsic to X-chromosome DNA, but can also occur on autosomes possessing the Xic...

..In addition to cloning the sm gene, we have mapped three modifiers of sm, for which we suggest possible candidate genes...

..1 at low levels if at all. The relatively abundant expression of mH2A1 in both sexes suggests that mH2A1 has functions in addition to a possible involvement in X chromosome inactivation...

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..Xist had to be activated within 48 hr of differentiation to effect silencing, suggesting that reversible repression by Xist is a required initiation step that might occur during normal X inactivation in female cells...

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..However, these mutant cells were eliminated quickly from the brain within 3 weeks of postnatal life. Thus, hypomethylated CNS neurons were impaired functionally and were selected against at postnatal stages...

..These results suggest that MeCP2 may be important for neuronal maintenance in the developing and in the mature primate prefrontal cortex, consistent with the previously reported phenotype of MeCP2-null mutant mice...

..These data imply that even apparently normal cloned animals may have subtle abnormalities in gene expression...

..These cell lines may represent developing neocortical neuroblasts blocked from complete differentiation, and they should be useful in the isolation and analysis of genes involved in early neocortical development...

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..Further in vitro analysis of cell spreading and migration suggests that alpha 1 beta 1 is not required for binding to collagen I and implicates a third receptor, possibly integrin alpha 3 beta 1, in collagen I binding...

..This program attempts to define the biological parameters which limit the nuclear cloning approach. ..

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..Aim 3 will use nuclear transplantation as a criterion to define the genetic and epigenetic alterations of the cancer cell genome that interfere with reversion to pluripotency. ..

..Aim 3 will use nuclear transplantation as a criterion to define the genetic and epigenetic alterations of the cancer cell genome that interfere with reversion to pluripotency. ..

..To investigate a possible causal relation between methylation and gene control we will compare gene expression in matched cell lines where due to inducible Dnmtl deletion the genome is either normal or hypomethylated. ..

..Once the experimental obstacles have been overcome, it is our long-term goal to use patient-specific iPS cell lines to study the basis of complex human diseases. ..