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Hochedlinger, Konrad

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Hochedlinger

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Konrad

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Hochedlinger, Konrad

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Author's Publications: search.filters.isAuthorOfPublication.2081da12-f7cb-4ce7-b78c-95e911c89afb

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    H3K36 methylation maintains cell identity by regulating opposing lineage programmes
    (Springer Science and Business Media LLC, 2023-07-17) Hoetker, Michael; Yagi, Masaki; Di Stefano, Bruno; Langerman, Justin; Cristea, Simona; Wong, Lai Ping; Huebner, Aaron J; Charlton, Jocelyn; Deng, Weixian; Haggerty, Chuck; Sadreyev, Ruslan I; Meissner, Alexander; Michor, Franziska; Plath, Kathrin; Hochedlinger, Konrad
    The epigenetic mechanisms that maintain differentiated cell states remain largely unexplored. Here, we employed histone mutants to uncover a crucial role for H3K36-methylation in the maintenance of cell identities across diverse developmental contexts. Focusing on the experimental induction of pluripotency, we show that H3K36M-mediated depletion of H3K36-methylation endows fibroblasts with a plastic state poised to acquire pluripotency in nearly all cells. At a cellular level, H3K36M facilitates epithelial plasticity by rendering fibroblasts insensitive to TGF signals. At a molecular level, H3K36M enables the decommissioning of mesenchymal enhancers and the parallel activation of epithelial/stem cell enhancers. This enhancer rewiring is Tet-dependent and redirects Sox2 from promiscuous somatic to pluripotency targets. Our findings reveal a previously unappreciated dual role for H3K36-methylation in the maintenance of cell identity by integrating a crucial developmental pathway into sustained expression of cell type-specific programs, and by opposing the expression of alternative lineage programs through enhancer methylation.
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    Mediator Subunit Med28 Is Essential for Mouse Peri-Implantation Development and Pluripotency
    (Public Library of Science, 2015) Li, Lin; Walsh, Ryan M.; Wagh, Vilas; James, Marianne F.; Beauchamp, Roberta L.; Chang, Yuh-Shin; Gusella, James; Hochedlinger, Konrad; Ramesh, Vijaya
    The multi-subunit mammalian Mediator complex acts as an integrator of transcriptional regulation by RNA Polymerase II, and has emerged as a master coordinator of development and cell fate determination. We previously identified the Mediator subunit, MED28, as a cytosolic binding partner of merlin, the Neurofibromatosis 2 (NF2) tumor suppressor, and thus MED28 is distinct in having a cytosolic role as an NF2 interacting protein as well as a nuclear role as a Mediator complex subunit. Although limited in vitro studies have been performed on MED28, its in vivo function remains unknown. Employing a knockout mouse model, we describe for the first time the requirement for Med28 in the developing mouse embryo. Med28-deficiency causes peri-implantation lethality resulting from the loss of pluripotency of the inner cell mass accompanied by reduced expression of key pluripotency transcription factors Oct4 and Nanog. Further, overexpression of Med28 in mouse embryonic fibroblasts enhances the efficiency of their reprogramming to pluripotency. Cre-mediated inactivation of Med28 in induced pluripotent stem cells shows that Med28 is required for their survival. Intriguingly, heterozygous loss of Med28 results in differentiation of induced pluripotent stem cells into extraembryonic trophectoderm and primitive endoderm lineages. Our findings document the essential role of Med28 in the developing embryo as well as in acquisition and maintenance of pluripotency during reprogramming.
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    Reduced MEK inhibition preserves genomic stability in naïve human ES cells
    (Springer Science and Business Media LLC, 2018-08-09) Di Stefano, Bruno; Hochedlinger, Konrad
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    Direct Reprogramming of Mouse Fibroblasts into Functional Skeletal Muscle Progenitors
    (Elsevier, 2018) Bar-Nur, Ori; Gerli, Mattia F.M.; Di Stefano, Bruno; Almada, Albert; Galvin, Amy; Coffey, Amy; Huebner, Aaron; Feige, Peter; Verheul, Cassandra; Cheung, Priscilla; Payzin-Dogru, Duygu; Paisant, Sylvain; Anselmo, Anthony; Sadreyev, Ruslan; Ott, Harald; Tajbakhsh, Shahragim; Rudnicki, Michael A.; Wagers, Amy; Hochedlinger, Konrad
    Summary Skeletal muscle harbors quiescent stem cells termed satellite cells and proliferative progenitors termed myoblasts, which play pivotal roles during muscle regeneration. However, current technology does not allow permanent capture of these cell populations in vitro. Here, we show that ectopic expression of the myogenic transcription factor MyoD, combined with exposure to small molecules, reprograms mouse fibroblasts into expandable induced myogenic progenitor cells (iMPCs). iMPCs express key skeletal muscle stem and progenitor cell markers including Pax7 and Myf5 and give rise to dystrophin-expressing myofibers upon transplantation in vivo. Notably, a subset of transplanted iMPCs maintain Pax7 expression and sustain serial regenerative responses. Similar to satellite cells, iMPCs originate from Pax7+ cells and require Pax7 itself for maintenance. Finally, we show that myogenic progenitor cell lines can be established from muscle tissue following small-molecule exposure alone. This study thus reports on a robust approach to derive expandable myogenic stem/progenitor-like cells from multiple cell types.
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    Lgr5-Positive Supporting Cells Generate New Hair Cells in the Postnatal Cochlea
    (Elsevier, 2014) Bramhall, Naomi F.; Shi, Fuxin; Arnold, Katrin; Hochedlinger, Konrad; Edge, Albert S.B.
    Summary The prevalence of hearing loss after damage to the mammalian cochlea has been thought to be due to a lack of spontaneous regeneration of hair cells, the primary receptor cells for sound. Here, we show that supporting cells, which surround hair cells in the normal cochlear epithelium, differentiate into new hair cells in the neonatal mouse following ototoxic damage. Using lineage tracing, we show that new hair cells, predominantly outer hair cells, arise from Lgr5-expressing inner pillar and third Deiters cells and that new hair cell generation is increased by pharmacological inhibition of Notch. These data suggest that the neonatal mammalian cochlea has some capacity for hair cell regeneration following damage alone and that Lgr5-positive cells act as hair cell progenitors in the cochlea.
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    Rearranging the chromatin for pluripotency
    (Landes Bioscience, 2014) Ferrari, Francesco; Apostolou, Effie; Park, Peter; Hochedlinger, Konrad
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    Cell Type of Origin Influences the Molecular and Functional Properties of Mouse Induced Pluripotent Stem Cells
    (Nature Publishing Group, 2010) Polo, Jose M.; Liu, Susanna; Figueroa, Maria Eugenia; Kulalert, Warakorn; Eminli, Sarah; Tan, Kah Yong; Apostolou, Effie; Stadtfeld, Matthias; Li, Yushan; Shioda, Toshihiro; Natesan, Sridaran; Wagers, Amy; Melnick, Ari; Evans, Todd; Hochedlinger, Konrad
    Induced pluripotent stem cells (iPSCs) have been derived from various somatic cell populations through ectopic expression of defined factors. It remains unclear whether iPSCs generated from different cell types are molecularly and functionally similar. Here we show that iPSCs obtained from mouse fibroblasts, hematopoietic and myogenic cells exhibit distinct transcriptional and epigenetic patterns. Moreover, we demonstrate that cellular origin influences the in vitro differentiation potentials of iPSCs into embryoid bodies and different hematopoietic cell types. Notably, continuous passaging of iPSCs largely attenuates these differences. Our results suggest that early-passage iPSCs retain a transient epigenetic memory of their somatic cells of origin, which manifests as differential gene expression and altered differentiation capacity. These observations may influence ongoing attempts to use iPSCs for disease modeling and could also be exploited in potential therapeutic applications to enhance differentiation into desired cell lineages.
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    ISSCR 2013: Back to Bean Town
    (Elsevier, 2013) Brack, Andrew S.; Hochedlinger, Konrad
    The International Society for Stem Cell Research 11th Annual Meeting was held in Boston in June 2013, bringing together just over 4000 attendees. An emphasis on therapeutic applications in many talks reflected the maturation of the stem cell field from its origins in basic science to one that is beginning to show therapeutic promise.
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    A Serial shRNA Screen for Roadblocks to Reprogramming Identifies the Protein Modifier SUMO2
    (Elsevier, 2016) Borkent, Marti; Bennett, Brian D.; Lackford, Brad; Bar-Nur, Ori; Brumbaugh, Justin; Wang, Li; Du, Ying; Fargo, David C.; Apostolou, Effie; Cheloufi, Sihem; Maherali, Nimet; Elledge, Stephen J.; Hu, Guang; Hochedlinger, Konrad
    Summary The generation of induced pluripotent stem cells (iPSCs) from differentiated cells following forced expression of OCT4, KLF4, SOX2, and C-MYC (OKSM) is slow and inefficient, suggesting that transcription factors have to overcome somatic barriers that resist cell fate change. Here, we performed an unbiased serial shRNA enrichment screen to identify potent repressors of somatic cell reprogramming into iPSCs. This effort uncovered the protein modifier SUMO2 as one of the strongest roadblocks to iPSC formation. Depletion of SUMO2 both enhances and accelerates reprogramming, yielding transgene-independent, chimera-competent iPSCs after as little as 38 hr of OKSM expression. We further show that the SUMO2 pathway acts independently of exogenous C-MYC expression and in parallel with small-molecule enhancers of reprogramming. Importantly, suppression of SUMO2 also promotes the generation of human iPSCs. Together, our results reveal sumoylation as a crucial post-transcriptional mechanism that resists the acquisition of pluripotency from fibroblasts using defined factors.
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    Distinct, strict requirements for Gfi-1b in adult bone marrow red cell and platelet generation
    (The Rockefeller University Press, 2014) Foudi, Adlen; Kramer, Danny; Qin, Jinzhong; Ye, Denise; Behlich, Anna-Sophie; Mordecai, Scott; Preffer, Frederic; Amzallag, Arnaud; Ramaswamy, Sridhar; Hochedlinger, Konrad; Orkin, Stuart; Hock, Hanno
    The zinc finger transcriptional repressor Gfi-1b is essential for erythroid and megakaryocytic development in the embryo. Its roles in the maintenance of bone marrow erythropoiesis and thrombopoiesis have not been defined. We investigated Gfi-1b’s adult functions using a loxP-flanked Gfi-1b allele in combination with a novel doxycycline-inducible Cre transgene that efficiently mediates recombination in the bone marrow. We reveal strict, lineage-intrinsic requirements for continuous adult Gfi-1b expression at two distinct critical stages of erythropoiesis and megakaryopoiesis. Induced disruption of Gfi-1b was lethal within 3 wk with severely reduced hemoglobin levels and platelet counts. The erythroid lineage was arrested early in bipotential progenitors, which did not give rise to mature erythroid cells in vitro or in vivo. Yet Gfi-1b−/− progenitors had initiated the erythroid program as they expressed many lineage-restricted genes, including Klf1/Eklf and Erythropoietin receptor. In contrast, the megakaryocytic lineage developed beyond the progenitor stage in Gfi-1b’s absence and was arrested at the promegakaryocyte stage, after nuclear polyploidization, but before cytoplasmic maturation. Genome-wide analyses revealed that Gfi-1b directly regulates a wide spectrum of megakaryocytic and erythroid genes, predominantly repressing their expression. Together our study establishes Gfi-1b as a master transcriptional repressor of adult erythropoiesis and thrombopoiesis.