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rudolf jaenisch

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...
September 26, 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...
July 13, 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 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
Ana C D'Alessio, Zi Peng Fan, Katherine J Wert, Petr Baranov, Malkiel A Cohen, Janmeet S Saini, Evan Cohick, Carol Charniga, Daniel Dadon, Nancy M Hannett, Michael J Young, Sally Temple, Rudoff Jaenisch, Tong Ihn Lee, Richard A Young
Hundreds of transcription factors (TFs) are expressed in each cell type, but cell identity can be induced through the activity of just a small number of core TFs. Systematic identification of these core TFs for a wide variety of cell types is currently lacking and would establish a foundation for understanding the transcriptional control of cell identity in development, disease, and cell-based therapy. Here, we describe a computational approach that generates an atlas of candidate core TFs for a broad spectrum of human cells...
November 10, 2015: Stem Cell Reports
Laura Wiehle, Günter Raddatz, Tanja Musch, Meelad M Dawlaty, Rudolf Jaenisch, Frank Lyko, Achim Breiling
DNA methylation is a dynamic epigenetic modification with an important role in cell fate specification and reprogramming. The Ten eleven translocation (Tet) family of enzymes converts 5-methylcytosine to 5-hydroxymethylcytosine, which promotes passive DNA demethylation and functions as an intermediate in an active DNA demethylation process. Tet1/Tet2 double-knockout mice are characterized by developmental defects and epigenetic instability, suggesting a requirement for Tet-mediated DNA demethylation for the proper regulation of gene expression during differentiation...
February 2016: Molecular and Cellular Biology
Zhigang Zhao, Li Chen, Meelad M Dawlaty, Feng Pan, Ophelia Weeks, Yuan Zhou, Zeng Cao, Hui Shi, Jiapeng Wang, Li Lin, Shi Chen, Weiping Yuan, Zhaohui Qin, Hongyu Ni, Stephen D Nimer, Feng-Chun Yang, Rudolf Jaenisch, Peng Jin, Mingjiang Xu
TET1/2/3 are methylcytosine dioxygenases that regulate cytosine hydroxymethylation. Tet1/2 are abundantly expressed in HSC/HPCs and are implicated in hematological malignancies. Tet2 deletion in mice causes myeloid malignancies, while Tet1-null mice develop B cell lymphoma after an extended period of latency. Interestingly, TET1/2 are often concomitantly downregulated in acute B-lymphocytic leukemia. Here, we investigated the overlapping and non-redundant functions of Tet1/2 using Tet1/2 double-knockout (DKO) mice...
November 24, 2015: Cell Reports
Yonatan Stelzer, Chikdu Shakti Shivalila, Frank Soldner, Styliani Markoulaki, Rudolf Jaenisch
Mammalian DNA methylation plays an essential role in development. To date, only snapshots of different mouse and human cell types have been generated, providing a static view on DNA methylation. To enable monitoring of methylation status as it changes over time, we establish a reporter of genomic methylation (RGM) that relies on a minimal imprinted gene promoter driving a fluorescent protein. We show that insertion of RGM proximal to promoter-associated CpG islands reports the gain or loss of DNA methylation...
September 24, 2015: Cell
Rudolf Jaenisch, Ushma S Neill
No abstract text is available yet for this article.
September 2015: Journal of Clinical Investigation
Ulf Dettmer, Andrew J Newman, Frank Soldner, Eric S Luth, Nora C Kim, Victoria E von Saucken, John B Sanderson, Rudolf Jaenisch, Tim Bartels, Dennis Selkoe
No abstract text is available yet for this article.
2015: Nature Communications
Szu-Yu Kuo, Adam B Castoreno, Leslie N Aldrich, Kara G Lassen, Gautam Goel, Vlado Dančík, Petric Kuballa, Isabel Latorre, Kara L Conway, Sovan Sarkar, Dorothea Maetzel, Rudolf Jaenisch, Paul A Clemons, Stuart L Schreiber, Alykhan F Shamji, Ramnik J Xavier
Studies of human genetics and pathophysiology have implicated the regulation of autophagy in inflammation, neurodegeneration, infection, and autoimmunity. These findings have motivated the use of small-molecule probes to study how modulation of autophagy affects disease-associated phenotypes. Here, we describe the discovery of the small-molecule probe BRD5631 that is derived from diversity-oriented synthesis and enhances autophagy through an mTOR-independent pathway. We demonstrate that BRD5631 affects several cellular disease phenotypes previously linked to autophagy, including protein aggregation, cell survival, bacterial replication, and inflammatory cytokine production...
August 4, 2015: Proceedings of the National Academy of Sciences of the United States of America
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