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rudolf jaenisch

X Shawn Liu, Hao Wu, Marine Krzisch, Xuebing Wu, John Graef, Julien Muffat, Denes Hnisz, Charles H Li, Bingbing Yuan, Chuanyun Xu, Yun Li, Dan Vershkov, Angela Cacace, Richard A Young, Rudolf Jaenisch
Fragile X syndrome (FXS), the most common genetic form of intellectual disability in males, is caused by silencing of the FMR1 gene associated with hypermethylation of the CGG expansion mutation in the 5' UTR of FMR1 in FXS patients. Here, we applied recently developed DNA methylation editing tools to reverse this hypermethylation event. Targeted demethylation of the CGG expansion by dCas9-Tet1/single guide RNA (sgRNA) switched the heterochromatin status of the upstream FMR1 promoter to an active chromatin state, restoring a persistent expression of FMR1 in FXS iPSCs...
February 8, 2018: Cell
Abraham S Weintraub, Charles H Li, Alicia V Zamudio, Alla A Sigova, Nancy M Hannett, Daniel S Day, Brian J Abraham, Malkiel A Cohen, Behnam Nabet, Dennis L Buckley, Yang Eric Guo, Denes Hnisz, Rudolf Jaenisch, James E Bradner, Nathanael S Gray, Richard A Young
There is considerable evidence that chromosome structure plays important roles in gene control, but we have limited understanding of the proteins that contribute to structural interactions between gene promoters and their enhancer elements. Large DNA loops that encompass genes and their regulatory elements depend on CTCF-CTCF interactions, but most enhancer-promoter interactions do not employ this structural protein. Here, we show that the ubiquitously expressed transcription factor Yin Yang 1 (YY1) contributes to enhancer-promoter structural interactions in a manner analogous to DNA interactions mediated by CTCF...
December 14, 2017: Cell
Chang-Ki Oh, Abdullah Sultan, Joseph Platzer, Nima Dolatabadi, Frank Soldner, Daniel B McClatchy, Jolene K Diedrich, John R Yates, Rajesh Ambasudhan, Tomohiro Nakamura, Rudolf Jaenisch, Stuart A Lipton
Mutations in PARK6 (PINK1) and PARK2 (Parkin) are linked to rare familial cases of Parkinson's disease (PD). Mutations in these genes result in pathological dysregulation of mitophagy, contributing to neurodegeneration. Here, we report that environmental factors causing a specific posttranslational modification on PINK1 can mimic these genetic mutations. We describe a molecular mechanism for impairment of mitophagy via formation of S-nitrosylated PINK1 (SNO-PINK1). Mitochondrial insults simulating age- or environmental-related stress lead to increased SNO-PINK1, inhibiting its kinase activity...
November 21, 2017: Cell Reports
Stefan Semrau, Johanna E Goldmann, Magali Soumillon, Tarjei S Mikkelsen, Rudolf Jaenisch, Alexander van Oudenaarden
Gene expression heterogeneity in the pluripotent state of mouse embryonic stem cells (mESCs) has been increasingly well-characterized. In contrast, exit from pluripotency and lineage commitment have not been studied systematically at the single-cell level. Here we measure the gene expression dynamics of retinoic acid driven mESC differentiation from pluripotency to lineage commitment, using an unbiased single-cell transcriptomics approach. We find that the exit from pluripotency marks the start of a lineage transition as well as a transient phase of increased susceptibility to lineage specifying signals...
October 23, 2017: Nature Communications
Duanqing Pei, David W Beier, Ephrat Levy-Lahad, Gary Marchant, Janet Rossant, Juan Carlos Izpisua Belmonte, Robin Lovell-Badge, Rudolf Jaenisch, Alta Charo, David Baltimore
A recent National Academies report articulates a path forward for research, ethics, and governance of clinical applications involving genome editing. In light of recent human embryo editing developments, scientists and stakeholders from all nations should cooperate to take advantage of this historic opportunity for medicine and also basic human biology.
October 5, 2017: Cell Stem Cell
Arigela Harikumar, Raghu Ram Edupuganti, Matan Sorek, Gajendra Kumar Azad, Styliani Markoulaki, Petra Sehnalová, Soňa Legartová, Eva Bártová, Shlomit Farkash-Amar, Rudolf Jaenisch, Uri Alon, Eran Meshorer
Embryonic stem cells (ESCs), with their dual capacity to self-renew and differentiate, are commonly used to study differentiation, epigenetic regulation, lineage choices, and more. Using non-directed retroviral integration of a YFP/Cherry exon into mouse ESCs, we generated a library of over 200 endogenously tagged fluorescent fusion proteins and present several proof-of-concept applications of this library. We show the utility of this library to track proteins in living cells; screen for pluripotency-related factors; identify heterogeneously expressing proteins; measure the dynamics of endogenously labeled proteins; track proteins recruited to sites of DNA damage; pull down tagged fluorescent fusion proteins using anti-Cherry antibodies; and test for interaction partners...
October 10, 2017: Stem Cell Reports
Raghu Ram Edupuganti, Arigela Harikumar, Yair Aaronson, Alva Biran, Badi Sri Sailaja, Malka Nissim-Rafinia, Gajendra Kumar Azad, Malkiel A Cohen, Jung Eun Park, Chikdu S Shivalila, Styliani Markoulaki, Siu Kwan Sze, Rudolf Jaenisch, Eran Meshorer
Embryonic stem cells (ESCs) are regulated by pluripotency-related transcription factors in concert with chromatin regulators. To identify additional stem cell regulators, we screened a library of endogenously labeled fluorescent fusion proteins in mouse ESCs for fluorescence loss during differentiation. We identified SET, which displayed a rapid isoform shift during early differentiation from the predominant isoform in ESCs, SETα, to the primary isoform in differentiated cells, SETβ, through alternative promoters...
October 10, 2017: Stem Cell Reports
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
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