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rudolf jaenisch

Ethan S Sokol, Yu-Xiong Feng, Dexter X Jin, Minu D Tizabi, Daniel H Miller, Malkiel A Cohen, Sandhya Sanduja, Ferenc Reinhardt, Jai Pandey, Daphne A Superville, Rudolf Jaenisch, Piyush B Gupta
Advances in mammography have sparked an exponential increase in the detection of early-stage breast lesions, most commonly ductal carcinoma in situ (DCIS). More than 50% of DCIS lesions are benign and will remain indolent, never progressing to invasive cancers. However, the factors that promote DCIS invasion remain poorly understood. Here, we show that SMARCE1 is required for the invasive progression of DCIS and other early-stage tumors. We show that SMARCE1 drives invasion by regulating the expression of secreted proteases that degrade basement membrane, an ECM barrier surrounding all epithelial tissues...
April 18, 2017: Proceedings of the National Academy of Sciences of the United States of America
Jian Feng, Catherine J Pena, Immanuel Purushothaman, Olivia Engmann, Deena Walker, Amber N Brown, Orna Issler, Marie Doyle, Eileen Harrigan, Ezekiell Mouzon, Vincent Vialou, Li Shen, Meelad M Dawlaty, Rudolf Jaenisch, Eric J Nestler
Depression is a leading cause of disease burden, yet current therapies fully treat <50% of affected individuals. Increasing evidence implicates epigenetic mechanisms in depression and antidepressant action. Here we examined a possible role for the DNA dioxygenase, ten-eleven translocation protein 1 (TET1), in depression-related behavioral abnormalities. We applied chronic social defeat stress, an ethologically validated mouse model of depression-like behaviors, and examined Tet1 expression changes in nucleus accumbens (NAc), a key brain reward region...
July 2017: Neuropsychopharmacology: Official Publication of the American College of Neuropsychopharmacology
Yun Li, Julien Muffat, Attya Omer, Irene Bosch, Madeline A Lancaster, Mriganka Sur, Lee Gehrke, Juergen A Knoblich, Rudolf Jaenisch
An expansion of the cerebral neocortex is thought to be the foundation for the unique intellectual abilities of humans. It has been suggested that an increase in the proliferative potential of neural progenitors (NPs) underlies the expansion of the cortex and its convoluted appearance. Here we show that increasing NP proliferation induces expansion and folding in an in vitro model of human corticogenesis. Deletion of PTEN stimulates proliferation and generates significantly larger and substantially folded cerebral organoids...
March 2, 2017: Cell Stem Cell
Anna Sahakyan, Rachel Kim, Constantinos Chronis, Shan Sabri, Giancarlo Bonora, Thorold W Theunissen, Edward Kuoy, Justin Langerman, Amander T Clark, Rudolf Jaenisch, Kathrin Plath
Naive human embryonic stem cells (hESCs) can be derived from primed hESCs or directly from blastocysts, but their X chromosome state has remained unresolved. Here, we show that the inactive X chromosome (Xi) of primed hESCs was reactivated in naive culture conditions. Like cells of the blastocyst, the resulting naive cells contained two active X chromosomes with XIST expression and chromosome-wide transcriptional dampening and initiated XIST-mediated X inactivation upon differentiation. Both establishment of and exit from the naive state (differentiation) happened via an XIST-negative XaXa intermediate...
January 5, 2017: Cell Stem Cell
Jun Wu, Henry T Greely, Rudolf Jaenisch, Hiromitsu Nakauchi, Janet Rossant, Juan Carlos Izpisua Belmonte
Chimaeras are both monsters of the ancient imagination and a long-established research tool. Recent advances, particularly those dealing with the identification and generation of various kinds of stem cells, have broadened the repertoire and utility of mammalian interspecies chimaeras and carved out new paths towards understanding fundamental biology as well as potential clinical applications.
December 1, 2016: Nature
Abhishek Banerjee, Rajeev V Rikhye, Vincent Breton-Provencher, Xin Tang, Chenchen Li, Keji Li, Caroline A Runyan, Zhanyan Fu, Rudolf Jaenisch, Mriganka Sur
Rett syndrome (RTT) arises from loss-of-function mutations in methyl-CpG binding protein 2 gene (Mecp2), but fundamental aspects of its physiological mechanisms are unresolved. Here, by whole-cell recording of synaptic responses in MeCP2 mutant mice in vivo, we show that visually driven excitatory and inhibitory conductances are both reduced in cortical pyramidal neurons. The excitation-to-inhibition (E/I) ratio is increased in amplitude and prolonged in time course. These changes predict circuit-wide reductions in response reliability and selectivity of pyramidal neurons to visual stimuli, as confirmed by two-photon imaging...
November 15, 2016: Proceedings of the National Academy of Sciences of the United States of America
Julien Muffat, Yun Li, Rudolf Jaenisch
In vitro differentiation of human pluripotent stem cells provides a systematic platform to investigate the physiological development and function of the human nervous system, as well as the etiology and consequence when these processes go awry. Recent development in three-dimensional (3D) organotypic culture systems allows modeling of the complex structure formation of the human CNS, and the intricate interactions between various resident neuronal and glial cell types. Combined with an ever-expanding genome editing and regulation toolkit such as CRISPR/Cas9, it is now a possibility to study human neurological disease in the relevant molecular, cellular and anatomical context...
December 2016: Current Opinion in Cell Biology
Julien Muffat, Yun Li, Bingbing Yuan, Maisam Mitalipova, Attya Omer, Sean Corcoran, Grisilda Bakiasi, Li-Huei Tsai, Patrick Aubourg, Richard M Ransohoff, Rudolf Jaenisch
Microglia, the only lifelong resident immune cells of the central nervous system (CNS), are highly specialized macrophages that have been recognized to have a crucial role in neurodegenerative diseases such as Alzheimer's, Parkinson's and adrenoleukodystrophy (ALD). However, in contrast to other cell types of the human CNS, bona fide microglia have not yet been derived from cultured human pluripotent stem cells. Here we establish a robust and efficient protocol for the rapid production of microglia-like cells from human (h) embryonic stem (ES) and induced pluripotent stem (iPS) cells that uses defined serum-free culture conditions...
November 2016: Nature Medicine
X Shawn Liu, Hao Wu, Xiong Ji, Yonatan Stelzer, Xuebing Wu, Szymon Czauderna, Jian Shu, Daniel Dadon, Richard A Young, Rudolf Jaenisch
Mammalian DNA methylation is a critical epigenetic mechanism orchestrating gene expression networks in many biological processes. However, investigation of the functions of specific methylation events remains challenging. Here, we demonstrate that fusion of Tet1 or Dnmt3a with a catalytically inactive Cas9 (dCas9) enables targeted DNA methylation editing. Targeting of the dCas9-Tet1 or -Dnmt3a fusion protein to methylated or unmethylated promoter sequences caused activation or silencing, respectively, of an endogenous reporter...
September 22, 2016: Cell
Thorold W Theunissen, Marc Friedli, Yupeng He, Evarist Planet, Ryan C O'Neil, Styliani Markoulaki, Julien Pontis, Haoyi Wang, Alexandra Iouranova, Michaël Imbeault, Julien Duc, Malkiel A Cohen, Katherine J Wert, Rosa Castanon, Zhuzhu Zhang, Yanmei Huang, Joseph R Nery, Jesse Drotar, Tenzin Lungjangwa, Didier Trono, Joseph R Ecker, Rudolf Jaenisch
Recent studies have aimed to convert cultured human pluripotent cells to a naive state, but it remains unclear to what extent the resulting cells recapitulate in vivo naive pluripotency. Here we propose a set of molecular criteria for evaluating the naive human pluripotent state by comparing it to the human embryo. We show that transcription of transposable elements provides a sensitive measure of the concordance between pluripotent stem cells and early human development. We also show that induction of the naive state is accompanied by genome-wide DNA hypomethylation, which is reversible except at imprinted genes, and that the X chromosome status resembles that of the human preimplantation embryo...
October 6, 2016: Cell Stem Cell
Parker B Antin
No abstract text is available yet for this article.
July 2016: Developmental Dynamics: An Official Publication of the American Association of Anatomists
Dirk Hockemeyer, Rudolf Jaenisch
It is extremely rare for a single experiment to be so impactful and timely that it shapes and forecasts the experiments of the next decade. Here, we review how two such experiments-the generation of human induced pluripotent stem cells (iPSCs) and the development of CRISPR/Cas9 technology-have fundamentally reshaped our approach to biomedical research, stem cell biology, and human genetics. We will also highlight the previous knowledge that iPSC and CRISPR/Cas9 technologies were built on as this groundwork demonstrated the need for solutions and the benefits that these technologies provided and set the stage for their success...
May 5, 2016: Cell Stem Cell
Frank Soldner, Yonatan Stelzer, Chikdu S Shivalila, Brian J Abraham, Jeanne C Latourelle, M Inmaculada Barrasa, Johanna Goldmann, Richard H Myers, Richard A Young, Rudolf Jaenisch
Genome-wide association studies (GWAS) have identified numerous genetic variants associated with complex diseases, but mechanistic insights are impeded by a lack of understanding of how specific risk variants functionally contribute to the underlying pathogenesis. It has been proposed that cis-acting effects of non-coding risk variants on gene expression are a major factor for phenotypic variation of complex traits and disease susceptibility. Recent genome-scale epigenetic studies have highlighted the enrichment of GWAS-identified variants in regulatory DNA elements of disease-relevant cell types...
May 5, 2016: Nature
Denes Hnisz, Abraham S Weintraub, Daniel S Day, Anne-Laure Valton, Rasmus O Bak, Charles H Li, Johanna Goldmann, Bryan R Lajoie, Zi Peng Fan, Alla A Sigova, Jessica Reddy, Diego Borges-Rivera, Tong Ihn Lee, Rudolf Jaenisch, Matthew H Porteus, Job Dekker, Richard A Young
Oncogenes are activated through well-known chromosomal alterations such as gene fusion, translocation, and focal amplification. In light of recent evidence that the control of key genes depends on chromosome structures called insulated neighborhoods, we investigated whether proto-oncogenes occur within these structures and whether oncogene activation can occur via disruption of insulated neighborhood boundaries in cancer cells. We mapped insulated neighborhoods in T cell acute lymphoblastic leukemia (T-ALL) and found that tumor cell genomes contain recurrent microdeletions that eliminate the boundary sites of insulated neighborhoods containing prominent T-ALL proto-oncogenes...
March 25, 2016: Science
Malkiel A Cohen, Katherine J Wert, Johanna Goldmann, Styliani Markoulaki, Yosef Buganim, Dongdong Fu, Rudolf Jaenisch
The neural crest (NC) represents multipotent cells that arise at the interphase between ectoderm and prospective epidermis of the neurulating embryo. The NC has major clinical relevance because it is involved in both inherited and acquired developmental abnormalities. The aim of this study was to establish an experimental platform that would allow for the integration of human NC cells (hNCCs) into the gastrulating mouse embryo. NCCs were derived from pluripotent mouse, rat, and human cells and microinjected into embryonic-day-8...
February 9, 2016: Proceedings of the National Academy of Sciences of the United States of America
Xiong Ji, Daniel B Dadon, Benjamin E Powell, Zi Peng Fan, Diego Borges-Rivera, Sigal Shachar, Abraham S Weintraub, Denes Hnisz, Gianluca Pegoraro, Tong Ihn Lee, Tom Misteli, Rudolf Jaenisch, Richard A Young
In this study, we describe the 3D chromosome regulatory landscape of human naive and primed embryonic stem cells. To devise this map, we identified transcriptional enhancers and insulators in these cells and placed them within the context of cohesin-associated CTCF-CTCF loops using cohesin ChIA-PET data. The CTCF-CTCF loops we identified form a chromosomal framework of insulated neighborhoods, which in turn form topologically associating domains (TADs) that are largely preserved during the transition between the naive and primed states...
February 4, 2016: Cell Stem Cell
Alejandro De Los Angeles, Francesco Ferrari, Ruibin Xi, Yuko Fujiwara, Nissim Benvenisty, Hongkui Deng, Konrad Hochedlinger, Rudolf Jaenisch, Soohyun Lee, Harry G Leitch, M William Lensch, Ernesto Lujan, Duanqing Pei, Janet Rossant, Marius Wernig, Peter J Park, George Q Daley
No abstract text is available yet for this article.
March 17, 2016: Nature
Alejandro De Los Angeles, Francesco Ferrari, Yuko Fujiwara, Ronald Mathieu, Soohyun Lee, Semin Lee, Ho-Chou Tu, Samantha Ross, Stephanie Chou, Minh Nguyen, Zhaoting Wu, Thorold W Theunissen, Benjamin E Powell, Sumeth Imsoonthornruksa, Jiekai Chen, Marti Borkent, Vladislav Krupalnik, Ernesto Lujan, Marius Wernig, Jacob H Hanna, Konrad Hochedlinger, Duanqing Pei, Rudolf Jaenisch, Hongkui Deng, Stuart H Orkin, Peter J Park, George Q Daley
No abstract text is available yet for this article.
March 17, 2016: Nature
Konrad Hochedlinger, Rudolf Jaenisch
Induced pluripotency defines the process by which somatic cells are converted into induced pluripotent stem cells (iPSCs) upon overexpression of a small set of transcription factors. In this article, we put transcription factor-induced pluripotency into a historical context, review current methods to generate iPSCs, and discuss mechanistic insights that have been gained into the process of reprogramming. In addition, we focus on potential therapeutic applications of induced pluripotency and emerging technologies to efficiently engineer the genomes of human pluripotent cells for scientific and therapeutic purposes...
December 1, 2015: Cold Spring Harbor Perspectives in Biology
Kristen J Brennand, M Carol Marchetto, Nissim Benvenisty, Oliver Brüstle, Allison Ebert, Juan Carlos Izpisua Belmonte, Ajamete Kaykas, Madeline A Lancaster, Frederick J Livesey, Michael J McConnell, Ronald D McKay, Eric M Morrow, Alysson R Muotri, David M Panchision, Lee L Rubin, Akira Sawa, Frank Soldner, Hongjun Song, Lorenz Studer, Sally Temple, Flora M Vaccarino, Jun Wu, Pierre Vanderhaeghen, Fred H Gage, Rudolf Jaenisch
As a group, we met to discuss the current challenges for creating meaningful patient-specific in vitro models to study brain disorders. Although the convergence of findings between laboratories and patient cohorts provided us confidence and optimism that hiPSC-based platforms will inform future drug discovery efforts, a number of critical technical challenges remain. This opinion piece outlines our collective views on the current state of hiPSC-based disease modeling and discusses what we see to be the critical objectives that must be addressed collectively as a field...
December 8, 2015: Stem Cell Reports
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