Reprogramming

  • Article
    | Open Access

    KLF4, OCT4, SOX2 and MYC cooperate to reorganize chromatin during somatic cell reprogramming. Here the authors show that KLF4 forms a liquid-like biomolecular condensate that recruits OCT4 and SOX2, and that condensation of the isolated KLF4 DNA binding domain with DNA is enhanced by CpG methylation

    • Rajesh Sharma
    • , Kyoung-Jae Choi
    •  & Josephine C. Ferreon
  • Article
    | Open Access

    The mechanisms by which in vivo expression of the Yamanaka transcription factors (OSKM) renders somatic cells permissive for differentiation remain unclear. Here, the authors show that in vivo reprogramming using OSKM generates germ cell tumors and drives acquisition of totipotency-like features in somatic cells through DMRT1.

    • Jumpei Taguchi
    • , Hirofumi Shibata
    •  & Yasuhiro Yamada
  • Article
    | Open Access

    Cells in many tissues fuse into syncytia acquiring new functions. By investigating whether physical remodelling promotes differentiation, here, the authors show that plasma membrane diminution post-fusion causes transient nutrient stress that inhibits YAP1 activity and may reduce proliferation-promoting transcription.

    • Daniel Feliciano
    • , Carolyn M. Ott
    •  & Jennifer Lippincott-Schwartz
  • Article
    | Open Access

    Both A/B compartments and TADs are thought to be absent from the inactive X chromosome, but to be re-established with transcriptional reactivation and chromatin opening during X-reactivation. Here, the authors characterise gene reactivation, chromatin opening and chromosome topology during X-reactivation, observe A/B-like compartments on the inactive X that guide TAD formation independently of transcription during X-reactivation.

    • Moritz Bauer
    • , Enrique Vidal
    •  & Bernhard Payer
  • Article
    | Open Access

    Transcription factor over-expression-based cellular conversion methods often endure low conversion efficiency. Here the authors show how to increase conversion efficiency by combining a computational method for prioritizing more efficient TF combinations with a transposon-based genomic integration system for delivery.

    • Sascha Jung
    • , Evan Appleton
    •  & Antonio del Sol
  • Article
    | Open Access

    Although ulcerative colitis (UC) is a major type of inflammatory bowel disease, attempts to model it fully have fallen short. Here the authors use patient-derived iPS cells to develop a UC organoid model that recapitulates disease histological and functional features, and confirm the role of CXCL8/CXCR1 in pathogenesis.

    • Samaneh K. Sarvestani
    • , Steven Signs
    •  & Emina H. Huang
  • Article
    | Open Access

    Active and passive demethylation pathways have been implicated in the genome-wide erasure of 5mC accompanying mammalian preimplantation development. Here the authors reveal a recently evolved, mammalian-specific pathway in which global hypomethylation is achieved by the coupling of active and passive demethylation.

    • Christopher B. Mulholland
    • , Atsuya Nishiyama
    •  & Heinrich Leonhardt
  • Article
    | Open Access

    Adult stem cells are thought to be fate restricted to lineages distinct to their tissue of origin. Here, the authors demonstrate that Tp63 expressing epithelial stem cells from several disparate tissues can respond to skin morphogenetic signals and contribute to hair follicles, sebaceous glands and/or epidermis.

    • Stéphanie Claudinot
    • , Jun-Ichi Sakabe
    •  & Yann Barrandon
  • Article
    | Open Access

    The conditions to induce human hepatic progenitor cells from other cell types are unclear. Here, the authors reprogram human endothelial cells to hepatic progenitor cells by expressing FOXA3, HNF1A and HNF6, capable of giving rise to hepatocytes and cholangiocytes that reconstitute damaged liver tissues on transplantation.

    • Hiroki Inada
    • , Miyako Udono
    •  & Atsushi Suzuki
  • Article
    | Open Access

    Previous work suggested that histone demethylase JMJD3 is detrimental to somatic cell reprogramming. Here, the authors show that while JMJD3 has a context-independent detrimental effect on early stages of reprogramming, during late stages it activates epithelial and pluripotency genes together with Klf4.

    • Yinghua Huang
    • , Hui Zhang
    •  & Baoming Qin
  • Article
    | Open Access

    Epigenetic reprogramming is a hallmark of cancer. Here the authors find that resetting primed human embryonic stem cells to naïve state results in the acquisition of a DNA methylation landscape that mirrors the cancer DNA methylome and provides evidence that the transition to naïve pluripotency and oncogenic transformation share common epigenetic trajectories.

    • Hemalvi Patani
    • , Michael D. Rushton
    •  & Gabriella Ficz
  • Article
    | Open Access

    The downstream pathway regulating how TGF-beta affects pluripotency of human PSCs is unclear. Here, the authors find that transcription factor ZNF398 binds active promoters/enhancers together with the histone acetyltransferase EP300 and SMAD3, enabling expression of pluripotency and epithelial genes.

    • Irene Zorzan
    • , Marco Pellegrini
    •  & Graziano Martello
  • Article
    | Open Access

    The organisation of chromatin in somatic cell nuclear transfer (SCNT) embryos remains poorly understood. Here, the authors examine higher order chromatin structures of mouse SCNT embryos and provide insights into chromatin architecture reorganisation during SCNT embryo development.

    • Mo Chen
    • , Qianshu Zhu
    •  & Shaorong Gao
  • Article
    | Open Access

    Aging involves gradual loss of tissue function, and transcription factor (TF) expression can ameliorate this in progeroid mice. Here the authors show that transient TF expression reverses age-associated epigenetic marks, inflammatory profiles and restores regenerative potential in naturally aged human cells.

    • Tapash Jay Sarkar
    • , Marco Quarta
    •  & Vittorio Sebastiano
  • Article
    | Open Access

    Point mutations have been found in induced pluripotent stem cells (iPSCs) but when they arise is unclear. Here, the authors show that a G1/S cell cycle checkpoint deficiency transiently occurs early in genome reprogramming, suggesting a common developmental pathway between iPSC and tumorigenesis, and generate genetic burden-free human iPSCs.

    • Ryoko Araki
    • , Yuko Hoki
    •  & Masumi Abe
  • Article
    | Open Access

    The adult mammalian inner ear cells cannot regenerate nor proliferate. Here, the authors show that co-activation of Myc and NOTCH pathways can stimulate proliferation of inner ear sensory epithelial cells, which can be induced to become hair cell-like cells in vitro and in vivo.

    • Yilai Shu
    • , Wenyan Li
    •  & Zheng-Yi Chen
  • Article
    | Open Access

    Barriers underlying the inefficiency of reprogramming cells to pluripotency are poorly defined. Here the authors identify a transient interval soon after pluripotency exit that permits high-efficiency reprogramming and is facilitated by OCT4 bound elements displaying unique silencing behaviour during differentiation.

    • Sudhir Thakurela
    • , Camille Sindhu
    •  & Alexander Meissner
  • Article
    | Open Access

    Oct4, along with Sox2 and Klf4 can induce pluripotency, but structurally similar factors like Oct6 cannot. Here, using pluripotency competent and incompetent factors, the authors show that Sox2 plays a dominant role in facilitating chromatin opening at Oct4 bound DNA early during reprogramming to pluripotency.

    • Vikas Malik
    • , Laura V. Glaser
    •  & Ralf Jauch
  • Article
    | Open Access

    Master transcription factors dominantly direct cell fate and barriers ensuring their tissue specific silencing are not clearly defined. Here, the authors demonstrate that inefficient targeted transactivation of Sox1 in neural progenitor cells is surmountable through targeted promoter demethylation using dCas9-Tet1.

    • Valentin Baumann
    • , Maximilian Wiesbeck
    •  & Stefan H. Stricker
  • Article
    | Open Access

    Fibroblasts can be directly reprogrammed to cardiomyocytes, but reprogramming is less efficient for adult compared to embryonic fibroblasts. Here, the authors find that inhibition of inflammation and Cox-2-prostaglandin-cAMP-IL-1β signaling enhances reprogramming efficiency of adult, but not embryonic fibroblasts.

    • Naoto Muraoka
    • , Kaori Nara
    •  & Masaki Ieda
  • Article
    | Open Access

    Animal studies have shown that the nutritional status of parents can predispose the offspring to obesity and obesity-related diseases. Here the authors show that cardiac dysfunction induced by a high-fat diet persists for two generations in Drosophila, and that targeted expression of ATGL/bmm in the offspring, as well as inhibition of H3K27 trimethylation, is cardioprotective.

    • Maria Clara Guida
    • , Ryan Tyge Birse
    •  & Rolf Bodmer
  • Article
    | Open Access

    HMGN1 and HMGN2 are ubiquitous nucleosome binding proteins. Here the authors provide evidence that HMGN proteins preferentially localize to chromatin regulatory sites to modulate the plasticity of the epigenetic landscape, proposing that HGMNs stabilize, rather than determine, cell identity.

    • Bing He
    • , Tao Deng
    •  & Michael Bustin
  • Article
    | Open Access

    In vitro culture has detrimental effects on transcriptomes and epigenetic programming of zygotes. Here the authors use microfluidic technology to co-culture bovine oviduct epithelial cells with zygotes and show that the transcriptomes and global methylation patterns of these zygotes are more similar to in vivo zygotes than to conventionally cultured zygotes.

    • Marcia A. M. M. Ferraz
    • , Hoon Suk Rho
    •  & Bart M. Gadella
  • Article
    | Open Access

    In vivo reprogramming of somatic cells is hampered by the need for vectors to express the OKSM factors in selected organs. Here the authors report new AAV-based vectors capable of in vivo reprogramming at low doses.

    • Elena Senís
    • , Lluc Mosteiro
    •  & Dirk Grimm
  • Article
    | Open Access

    CRISPRa is an attractive tool for cellular reprogramming due to its multiplexing capacity and direct targeting of genomic loci. Here the authors demonstrate the reprogramming of human fibroblasts into iPSCs, which is enhanced by targeting a conserved Alu-motif.

    • Jere Weltner
    • , Diego Balboa
    •  & Timo Otonkoski
  • Article
    | Open Access

    Uhrf1 is a known regulator of heterochromatin and DNA methylation in embryonic stem cells (ESCs). Here, the authors demonstrate that Uhrf1 acts together with the Set1/COMPASS complex regulator of active transcription to promote H3K4 methylation at bivalent loci and Uhrf1 loss results in disruption of differentiation.

    • Kun-Yong Kim
    • , Yoshiaki Tanaka
    •  & In-Hyun Park
  • Article
    | Open Access

    Sex differences in placental O-linked N-acetylglucosamine transferase (OGT) activity mediate the effects of prenatal stress on neurodevelopmental programming. Here authors provide evidence that OGT confers variation in vulnerability to prenatal insults by establishing sex-specific trophoblast gene expression via regulation of H3K27me3.

    • Bridget M. Nugent
    • , Carly M. O’Donnell
    •  & Tracy L. Bale
  • Article
    | Open Access

    Histone variant H3.3 is incorporated at transcriptionally active genes and is associated with active marks. Here, the authors investigate H3.3 deposition during reprogramming and find that initially H3.3 helps maintain parental cell fate and is later required for establishment of the cell lineages.

    • Hai-Tong Fang
    • , Chadi A. EL Farran
    •  & Yuin-Han Loh
  • Article
    | Open Access

    Induced pluripotent stem cells (iPSCs) have potential for regenerative medicine applications, but are generated with very low efficiency. Here, the authors show highly efficient reprogramming of human primary fibroblasts to iPSCs via the synergistic activity of synthetic modified mRNAs, mature miRNA mimics, and optimized culture methods.

    • Igor Kogut
    • , Sandra M. McCarthy
    •  & Ganna Bilousova
  • Article
    | Open Access

    The T-box transcription factor eomesodermin (EOMES) acts both in endoderm specification as well as heart development, suggesting context-specific function. Here, the authors show that dose-controlled EOMES induction is sufficient for cardiogenic programming of human pluripotent stem cells.

    • Martin J. Pfeiffer
    • , Roberto Quaranta
    •  & Boris Greber
  • Article
    | Open Access

    Derivation of human induced pluripotent stem cells (hiPSCs) produces primed hiPSCs that can in turn be converted to naive hiPSCs. Here, the authors directly reprogram somatic cells to form both naive and primed isogenic hiPSCs and confirm the similarity of naive hiPSCs to their in vivo counterparts.

    • Stéphanie Kilens
    • , Dimitri Meistermann
    •  & Matthew L. Albert
  • Article
    | Open Access

    X-chromosome inactivation is reversed in the mouse inner cell mass (ICM) through a mechanism that is not fully understood. Here, the authors investigate this process and characterize the contributions of the epigenetic landscape and transcription factors in X-linked gene reactivation dynamics.

    • Maud Borensztein
    • , Ikuhiro Okamoto
    •  & Edith Heard
  • Article
    | Open Access

    Priming of the adult mouse heart with Tβ4 activates dormant epicardium-derived cells to aid repair of injured myocardium. Here, Vieiraet al. explain this process and show that Tβ4 binds a chromatin remodeller BRG1 and activates Wt1, the key regulator of epicardial epithelial-to-mesenchymal transformation, by altering the epigenetic landscape of the Wt1 locus.

    • Joaquim Miguel Vieira
    • , Sara Howard
    •  & Paul R. Riley
  • Article
    | Open Access

    Tumour-specific T cells can be expandedin vitroand adoptively transferred for therapy, but this strategy is limited by induction of short-lived T cell populations. Here the authors activate Notch signalling in cultured mouse or human T cells, resulting in the production of a long-lived stem cell memory T cell population that can fight tumours in mice.

    • Taisuke Kondo
    • , Rimpei Morita
    •  & Akihiko Yoshimura
  • Article
    | Open Access

    The identification of master regulator genes that may be manipulatedin vitro to regulate reprogramming has been difficult. Here, the authors use a computational systems approach to identify three genes (FoxA1, Nkx3.1and the androgen receptor) that can reprogramme fibroblasts to prostate tissue.

    • Flaminia Talos
    • , Antonina Mitrofanova
    •  & Michael M. Shen
  • Article
    | Open Access

    Liver and pancreas cells arise from a common endoderm progenitor in the embryo, but what regulates their cell fate is unclear. Here, the authors show that expression of the Three-Amino-acid-Loop-Extension (TALE) homeobox TG-interacting factor 2 (TGIF2) in hepatocytes reprogrammes the cells to a pancreatic fate.

    • Nuria Cerdá-Esteban
    • , Heike Naumann
    •  & Francesca M. Spagnoli
  • Article
    | Open Access

    Schwann cells (SCs) myelinate peripheral nerve axons and offer opportunities for the treatment of injuries and demyelinating diseases but reliable and renewable sources of these cells are hard to come by. Here the authors reprogram rat, mouse and human fibroblasts into Schwann cells using two transcription factors.

    • Pietro Giuseppe Mazzara
    • , Luca Massimino
    •  & Vania Broccoli
  • Article
    | Open Access

    Land plants and metazoans are both able to reprogram differentiated cells to stem cells under certain circumstances. Here the authors show that the moss CSP1 protein, which shares conserved domains with the mammalian pluripotent stem cell factor Lin28, promotes reprogramming of leaf cells to apical stem cells.

    • Chen Li
    • , Yusuke Sako
    •  & Mitsuyasu Hasebe