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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
Jacqueline Deen, Martin W Weber, Thomas Jaenisch
No abstract text is available yet for this article.
August 2016: PLoS Neglected Tropical Diseases
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
Nadine Jaenisch, Lutz Liebmann, Madlen Guenther, Christian A Hübner, Christiane Frahm, Otto W Witte
Stroke survivors often recover from motor deficits, either spontaneously or with the support of rehabilitative training. Since tonic GABAergic inhibition controls network excitability, it may be involved in recovery. Middle cerebral artery occlusion in rodents reduces tonic GABAergic inhibition in the structurally intact motor cortex (M1). Transcript and protein abundance of the extrasynaptic GABAA-receptor complex α4β3δ are concurrently reduced (δ-GABAARs). In vivo and in vitro analyses show that stroke-induced glutamate release activates NMDA receptors, thereby reducing KCC2 transporters and down-regulates δ-GABAARs...
2016: Scientific Reports
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
Simone Jaenisch, Michelle Squire, Ross Butler, Roger Yazbeck
Oesophageal cancer is a significant cause of cancer related mortality, with increasing incidence worldwide. Ornithine decarboxylase (ODC) is an enzyme involved in polyamine synthesis and cellular proliferation, and ODC expression and activity has been implicated as a prognostic marker of oesophageal cancer. This study aimed to develop and optimise an in vitro (13)C-stable isotope assay for ODC activity as a non-invasive marker of oesophageal cancer. Experiments were performed in triplicate (n  =  3/group/cell line) using Caco2, HeLa, Flo-1, OE33, TE7 and OE21 cell lines (colorectal, cervical, oesophageal adenocarcinoma and oesophageal squamous carcinoma respectively)...
June 2016: Journal of Breath Research
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
Jane P Messina, Moritz Ug Kraemer, Oliver J Brady, David M Pigott, Freya M Shearer, Daniel J Weiss, Nick Golding, Corrine W Ruktanonchai, Peter W Gething, Emily Cohn, John S Brownstein, Kamran Khan, Andrew J Tatem, Thomas Jaenisch, Christopher Jl Murray, Fatima Marinho, Thomas W Scott, Simon I Hay
Zika virus was discovered in Uganda in 1947 and is transmitted by Aedes mosquitoes, which also act as vectors for dengue and chikungunya viruses throughout much of the tropical world. In 2007, an outbreak in the Federated States of Micronesia sparked public health concern. In 2013, the virus began to spread across other parts of Oceania and in 2015, a large outbreak in Latin America began in Brazil. Possible associations with microcephaly and Guillain-Barré syndrome observed in this outbreak have raised concerns about continued global spread of Zika virus, prompting its declaration as a Public Health Emergency of International Concern by the World Health Organization...
2016: ELife
Patrícia Brasil, Guilherme Amaral Calvet, André Machado Siqueira, Mayumi Wakimoto, Patrícia Carvalho de Sequeira, Aline Nobre, Marcel de Souza Borges Quintana, Marco Cesar Lima de Mendonça, Otilia Lupi, Rogerio Valls de Souza, Carolina Romero, Heruza Zogbi, Clarisse da Silveira Bressan, Simone Sampaio Alves, Ricardo Lourenço-de-Oliveira, Rita Maria Ribeiro Nogueira, Marilia Sá Carvalho, Ana Maria Bispo de Filippis, Thomas Jaenisch
BACKGROUND: In 2015, Brazil was faced with the cocirculation of three arboviruses of major public health importance. The emergence of Zika virus (ZIKV) presents new challenges to both clinicians and public health authorities. Overlapping clinical features between diseases caused by ZIKV, Dengue (DENV) and Chikungunya (CHIKV) and the lack of validated serological assays for ZIKV make accurate diagnosis difficult. METHODOLOGY / PRINCIPAL FINDINGS: The outpatient service for acute febrile illnesses in Fiocruz initiated a syndromic clinical observational study in 2007 to capture unusual presentations of DENV infections...
April 2016: PLoS Neglected Tropical Diseases
Thomas Jaenisch, Dong Thi Hoai Tam, Nguyen Tan Thanh Kieu, Tran Van Ngoc, Nguyen Tran Nam, Nguyen Van Kinh, Sophie Yacoub, Ngoun Chanpheaktra, Varun Kumar, Lucy Lum Chai See, Jameela Sathar, Ernesto Pleités Sandoval, Gabriela Maria Marón Alfaro, Ida Safitri Laksono, Yodi Mahendradhata, Malabika Sarker, Firoz Ahmed, Andrea Caprara, Bruno Souza Benevides, Ernesto T A Marques, Tereza Magalhaes, Patricia Brasil, Marco Netto, Adriana Tami, Sarah E Bethencourt, Maria Guzman, Cameron Simmons, Nguyen Thanh Ha Quyen, Laura Merson, Nguyen Thi Phuong Dung, Dorothea Beck, Marius Wirths, Marcel Wolbers, Phung Khanh Lam, Kerstin Rosenberger, Bridget Wills
BACKGROUND: The burden of dengue continues to increase globally, with an estimated 100 million clinically apparent infections occurring each year. Although most dengue infections are asymptomatic, patients can present with a wide spectrum of clinical symptoms ranging from mild febrile illness through to severe manifestations of bleeding, organ impairment, and hypovolaemic shock due to a systemic vascular leak syndrome. Clinical diagnosis of dengue and identification of which patients are likely to develop severe disease remain challenging...
2016: BMC Infectious Diseases
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
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