Rational Reprogramming of Cellular States by Combinatorial Perturbation.

Abstract:

:Ectopic expression of transcription factors (TFs) can reprogram cell state. However, because of the large combinatorial space of possible TF cocktails, it remains difficult to identify TFs that reprogram specific cell types. Here, we develop Reprogram-Seq to experimentally screen thousands of TF cocktails for reprogramming performance. Reprogram-Seq leverages organ-specific cell-atlas data with single-cell perturbation and computational analysis to predict, evaluate, and optimize TF combinations that reprogram a cell type of interest. Focusing on the cardiac system, we perform Reprogram-Seq on MEFs using an undirected library of 48 cardiac factors and, separately, a directed library of 10 epicardial-related TFs. We identify a combination of three TFs, which efficiently reprogram MEFs to epicardial-like cells that are transcriptionally, molecularly, morphologically, and functionally similar to primary epicardial cells. Reprogram-Seq holds promise to accelerate the generation of specific cell types for regenerative medicine.

journal_name

Cell Rep

journal_title

Cell reports

authors

Duan J,Li B,Bhakta M,Xie S,Zhou P,Munshi NV,Hon GC

doi

10.1016/j.celrep.2019.05.079

subject

Has Abstract

pub_date

2019-06-18 00:00:00

pages

3486-3499.e6

issue

12

issn

2211-1247

pii

S2211-1247(19)30708-9

journal_volume

27

pub_type

杂志文章
  • Linking Memories across Time via Neuronal and Dendritic Overlaps in Model Neurons with Active Dendrites.

    abstract::Memories are believed to be stored in distributed neuronal assemblies through activity-induced changes in synaptic and intrinsic properties. However, the specific mechanisms by which different memories become associated or linked remain a mystery. Here, we develop a simplified, biophysically inspired network model tha...

    journal_title:Cell reports

    pub_type: 杂志文章

    doi:10.1016/j.celrep.2016.10.015

    authors: Kastellakis G,Silva AJ,Poirazi P

    更新日期:2016-11-01 00:00:00

  • Transcriptomic Hallmarks of Tumor Plasticity and Stromal Interactions in Brain Metastasis.

    abstract::The brain is a major site of relapse for several cancers, yet deciphering the mechanisms of brain metastasis remains a challenge because of the complexity of the brain tumor microenvironment (TME). To define the molecular landscape of brain metastasis from intact tissue in vivo, we employ an RNA-sequencing-based appro...

    journal_title:Cell reports

    pub_type: 杂志文章

    doi:10.1016/j.celrep.2019.03.085

    authors: Wingrove E,Liu ZZ,Patel KD,Arnal-Estapé A,Cai WL,Melnick MA,Politi K,Monteiro C,Zhu L,Valiente M,Kluger HM,Chiang VL,Nguyen DX

    更新日期:2019-04-23 00:00:00

  • BMP4 Gene Therapy in Mature Mice Reduces BAT Activation but Protects from Obesity by Browning Subcutaneous Adipose Tissue.

    abstract::We examined the effect of Bone Morphogenetic Protein 4 (BMP4) on energy expenditure in adult mature mice by targeting the liver with adeno-associated viral (AAV) BMP4 vectors to increase circulating levels. We verified the direct effect of BMP4 in inducing a brown oxidative phenotype in differentiating preadipocytes i...

    journal_title:Cell reports

    pub_type: 杂志文章

    doi:10.1016/j.celrep.2017.07.020

    authors: Hoffmann JM,Grünberg JR,Church C,Elias I,Palsdottir V,Jansson JO,Bosch F,Hammarstedt A,Hedjazifar S,Smith U

    更新日期:2017-08-01 00:00:00

  • Early-Onset Hypertrophic Cardiomyopathy Mutations Significantly Increase the Velocity, Force, and Actin-Activated ATPase Activity of Human β-Cardiac Myosin.

    abstract::Hypertrophic cardiomyopathy (HCM) is a heritable cardiovascular disorder that affects 1 in 500 people. A significant percentage of HCM is attributed to mutations in β-cardiac myosin, the motor protein that powers ventricular contraction. This study reports how two early-onset HCM mutations, D239N and H251N, affect the...

    journal_title:Cell reports

    pub_type: 杂志文章

    doi:10.1016/j.celrep.2016.11.040

    authors: Adhikari AS,Kooiker KB,Sarkar SS,Liu C,Bernstein D,Spudich JA,Ruppel KM

    更新日期:2016-12-13 00:00:00

  • Three-Dimensional Study of Alzheimer's Disease Hallmarks Using the iDISCO Clearing Method.

    abstract::Amyloidosis is a major problem in over one hundred diseases, including Alzheimer's disease (AD). Using the iDISCO visualization method involving targeted molecular labeling, tissue clearing, and light-sheet microscopy, we studied plaque formation in the intact AD mouse brain at up to 27 months of age. We visualized am...

    journal_title:Cell reports

    pub_type: 杂志文章

    doi:10.1016/j.celrep.2016.06.060

    authors: Liebmann T,Renier N,Bettayeb K,Greengard P,Tessier-Lavigne M,Flajolet M

    更新日期:2016-07-26 00:00:00

  • Domain Model Explains Propagation Dynamics and Stability of Histone H3K27 and H3K36 Methylation Landscapes.

    abstract::Chromatin states must be maintained during cell proliferation to uphold cellular identity and genome integrity. Inheritance of histone modifications is central in this process. However, the histone modification landscape is challenged by incorporation of new unmodified histones during each cell cycle, and the principl...

    journal_title:Cell reports

    pub_type: 杂志文章

    doi:10.1016/j.celrep.2019.12.060

    authors: Alabert C,Loos C,Voelker-Albert M,Graziano S,Forné I,Reveron-Gomez N,Schuh L,Hasenauer J,Marr C,Imhof A,Groth A

    更新日期:2020-01-28 00:00:00

  • Comparative Gene Expression Analyses Reveal Distinct Molecular Signatures between Differentially Reprogrammed Cardiomyocytes.

    abstract::Cardiomyocytes derived from induced pluripotent stem cells (iPSC-CMs) or directly reprogrammed from non-myocytes (induced cardiomyocytes [iCMs]) are promising sources for heart regeneration or disease modeling. However, the similarities and differences between iPSC-CMs and iCMs are still unknown. Here, we performed tr...

    journal_title:Cell reports

    pub_type: 杂志文章

    doi:10.1016/j.celrep.2017.09.005

    authors: Zhou Y,Wang L,Liu Z,Alimohamadi S,Yin C,Liu J,Qian L

    更新日期:2017-09-26 00:00:00

  • H3K4me3 Demethylase Kdm5a Is Required for NK Cell Activation by Associating with p50 to Suppress SOCS1.

    abstract::The H3K4me3 demethylase Kdm5a regulates gene transcription and is implicated in carcinogenesis. However, the role of Kdm5a in innate immune response remains poorly understood. Here, we demonstrate that Kdm5a deficiency impairs activation of natural killer (NK) cells, with decreased IFN-γ production. Accordingly, Kdm5a...

    journal_title:Cell reports

    pub_type: 杂志文章

    doi:10.1016/j.celrep.2016.03.035

    authors: Zhao D,Zhang Q,Liu Y,Li X,Zhao K,Ding Y,Li Z,Shen Q,Wang C,Li N,Cao X

    更新日期:2016-04-12 00:00:00

  • MYO6 Regulates Spatial Organization of Signaling Endosomes Driving AKT Activation and Actin Dynamics.

    abstract::APPL1- and RAB5-positive signaling endosomes play a crucial role in the activation of AKT in response to extracellular stimuli. Myosin VI (MYO6) and two of its cargo adaptor proteins, GIPC and TOM1/TOM1L2, localize to these peripheral endosomes and mediate endosome association with cortical actin filaments. Loss of MY...

    journal_title:Cell reports

    pub_type: 杂志文章

    doi:10.1016/j.celrep.2017.05.048

    authors: Masters TA,Tumbarello DA,Chibalina MV,Buss F

    更新日期:2017-06-06 00:00:00

  • Presynaptic Endosomal Cathepsin D Regulates the Biogenesis of GABAergic Synaptic Vesicles.

    abstract::Presynaptic endosomes reportedly participate in synaptic vesicle (SV) recycling. However, it remains unclear whether they differentially regulate SV biogenesis and synaptic transmission in different types of synapses and how they are implicated in diseases. Using cryo-electron tomography and endocytic tracing, we unco...

    journal_title:Cell reports

    pub_type: 杂志文章

    doi:10.1016/j.celrep.2019.06.006

    authors: Li X,Qin L,Li Y,Yu H,Zhang Z,Tao C,Liu Y,Xue Y,Zhang X,Xu Z,Wang Y,Lou H,Tan Z,Saftig P,Chen Z,Xu T,Bi G,Duan S,Gao Z

    更新日期:2019-07-23 00:00:00

  • Disconnecting mitochondrial content from respiratory chain capacity in PGC-1-deficient skeletal muscle.

    abstract::The transcriptional coactivators PGC-1α and PGC-1β are widely thought to be required for mitochondrial biogenesis and fiber typing in skeletal muscle. Here, we show that mice lacking both PGC-1s in myocytes do indeed have profoundly deficient mitochondrial respiration but, surprisingly, have preserved mitochondrial co...

    journal_title:Cell reports

    pub_type: 杂志文章

    doi:10.1016/j.celrep.2013.04.023

    authors: Rowe GC,Patten IS,Zsengeller ZK,El-Khoury R,Okutsu M,Bampoh S,Koulisis N,Farrell C,Hirshman MF,Yan Z,Goodyear LJ,Rustin P,Arany Z

    更新日期:2013-05-30 00:00:00

  • Activation of Mevalonate Pathway via LKB1 Is Essential for Stability of Treg Cells.

    abstract::The function of regulatory T (Treg) cells depends on lipid oxidation. However, the molecular mechanism by which Treg cells maintain lipid metabolism after activation remains elusive. Liver kinase B1 (LKB1) acts as a coordinator by linking cellular metabolism to substrate AMP-activated protein kinase (AMPK). We show th...

    journal_title:Cell reports

    pub_type: 杂志文章

    doi:10.1016/j.celrep.2019.05.020

    authors: Timilshina M,You Z,Lacher SM,Acharya S,Jiang L,Kang Y,Kim JA,Chang HW,Kim KJ,Park B,Song JH,Ko HJ,Park YY,Ma MJ,Nepal MR,Jeong TC,Chung Y,Waisman A,Chang JH

    更新日期:2019-06-04 00:00:00

  • A Dendritic Golgi Satellite between ERGIC and Retromer.

    abstract::The local synthesis of transmembrane proteins underlies functional specialization of dendritic microdomains in neuronal plasticity. It is unclear whether these proteins have access to the complete machinery of the secretory pathway following local synthesis. In this study, we describe a probe called pGolt that allows ...

    journal_title:Cell reports

    pub_type: 杂志文章

    doi:10.1016/j.celrep.2015.12.024

    authors: Mikhaylova M,Bera S,Kobler O,Frischknecht R,Kreutz MR

    更新日期:2016-01-12 00:00:00

  • PHB3 Maintains Root Stem Cell Niche Identity through ROS-Responsive AP2/ERF Transcription Factors in Arabidopsis.

    abstract::The root stem cell niche, which is composed of four mitotically inactive quiescent center (QC) cells and the surrounding actively divided stem cells in Arabidopsis, is critical for growth and root development. Here, we demonstrate that the Arabidopsis prohibitin protein PHB3 is required for the maintenance of root ste...

    journal_title:Cell reports

    pub_type: 杂志文章

    doi:10.1016/j.celrep.2017.12.105

    authors: Kong X,Tian H,Yu Q,Zhang F,Wang R,Gao S,Xu W,Liu J,Shani E,Fu C,Zhou G,Zhang L,Zhang X,Ding Z

    更新日期:2018-01-30 00:00:00

  • HIV Triggers a cGAS-Dependent, Vpu- and Vpr-Regulated Type I Interferon Response in CD4+ T Cells.

    abstract::Several pattern-recognition receptors sense HIV-1 replication products and induce type I interferon (IFN-I) production under specific experimental conditions. However, it is thought that viral sensing and IFN induction are virtually absent in the main target cells of HIV-1 in vivo. Here, we show that activated CD4+ T ...

    journal_title:Cell reports

    pub_type: 杂志文章

    doi:10.1016/j.celrep.2016.09.023

    authors: Vermeire J,Roesch F,Sauter D,Rua R,Hotter D,Van Nuffel A,Vanderstraeten H,Naessens E,Iannucci V,Landi A,Witkowski W,Baeyens A,Kirchhoff F,Verhasselt B

    更新日期:2016-10-04 00:00:00

  • Long-Term Memory Engram Cells Are Established by c-Fos/CREB Transcriptional Cycling.

    abstract::Training-dependent increases in c-fos have been used to identify engram cells encoding long-term memories (LTMs). However, the interaction between transcription factors required for LTM, including CREB and c-Fos, and activating kinases such as phosphorylated ERK (pERK) in the establishment of memory engrams has been u...

    journal_title:Cell reports

    pub_type: 杂志文章

    doi:10.1016/j.celrep.2018.11.022

    authors: Miyashita T,Kikuchi E,Horiuchi J,Saitoe M

    更新日期:2018-12-04 00:00:00

  • Neutrophils Regulate Humoral Autoimmunity by Restricting Interferon-γ Production via the Generation of Reactive Oxygen Species.

    abstract::Here, we examine the mechanism by which plasmacytoid dendritic cells (pDCs) and type I interferons promote humoral autoimmunity. In an amyloid-induced experimental autoimmune model, neutrophil depletion enhanced anti-nuclear antibody development, which correlated with heightened IFN-γ production by natural killer (NK)...

    journal_title:Cell reports

    pub_type: 杂志文章

    doi:10.1016/j.celrep.2015.07.021

    authors: Huang X,Li J,Dorta-Estremera S,Di Domizio J,Anthony SM,Watowich SS,Popkin D,Liu Z,Brohawn P,Yao Y,Schluns KS,Lanier LL,Cao W

    更新日期:2015-08-18 00:00:00

  • Network-Targeted, Multi-site Direct Cortical Stimulation Enhances Working Memory by Modulating Phase Lag of Low-Frequency Oscillations.

    abstract::Working memory is mediated by the coordinated activation of frontal and parietal cortices occurring in the theta and alpha frequency ranges. Here, we test whether electrically stimulating frontal and parietal regions at the frequency of interaction is effective in modulating working memory. We identify working memory ...

    journal_title:Cell reports

    pub_type: 杂志文章

    doi:10.1016/j.celrep.2019.10.072

    authors: Alagapan S,Riddle J,Huang WA,Hadar E,Shin HW,Fröhlich F

    更新日期:2019-11-26 00:00:00

  • Small-Molecule and CRISPR Screening Converge to Reveal Receptor Tyrosine Kinase Dependencies in Pediatric Rhabdoid Tumors.

    abstract::Cancer is often seen as a disease of mutations and chromosomal abnormalities. However, some cancers, including pediatric rhabdoid tumors (RTs), lack recurrent alterations targetable by current drugs and need alternative, informed therapeutic options. To nominate potential targets, we performed a high-throughput small-...

    journal_title:Cell reports

    pub_type: 杂志文章

    doi:10.1016/j.celrep.2019.07.021

    authors: Oberlick EM,Rees MG,Seashore-Ludlow B,Vazquez F,Nelson GM,Dharia NV,Weir BA,Tsherniak A,Ghandi M,Krill-Burger JM,Meyers RM,Wang X,Montgomery P,Root DE,Bieber JM,Radko S,Cheah JH,Hon CS,Shamji AF,Clemons PA,Park PJ

    更新日期:2019-08-27 00:00:00

  • Chd5 requires PHD-mediated histone 3 binding for tumor suppression.

    abstract::Chromodomain Helicase DNA binding protein 5 (CHD5) is a tumor suppressor mapping to 1p36, a genomic region that is frequently deleted in human cancer. Although CHD5 belongs to the CHD family of chromatin-remodeling proteins, whether its tumor-suppressive role involves an interaction with chromatin is unknown. Here we ...

    journal_title:Cell reports

    pub_type: 杂志文章

    doi:10.1016/j.celrep.2012.12.009

    authors: Paul S,Kuo A,Schalch T,Vogel H,Joshua-Tor L,McCombie WR,Gozani O,Hammell M,Mills AA

    更新日期:2013-01-31 00:00:00

  • The KRAB Zinc Finger Protein Roma/Zfp157 Is a Critical Regulator of Cell-Cycle Progression and Genomic Stability.

    abstract::Regulation of DNA replication and cell division is essential for tissue growth and maintenance of genomic integrity and is particularly important in tissues that undergo continuous regeneration such as mammary glands. We have previously shown that disruption of the KRAB-domain zinc finger protein Roma/Zfp157 results i...

    journal_title:Cell reports

    pub_type: 杂志文章

    doi:10.1016/j.celrep.2016.03.078

    authors: Ho TLF,Guilbaud G,Blow JJ,Sale JE,Watson CJ

    更新日期:2016-04-26 00:00:00

  • Hepatic Leukemia Factor Maintains Quiescence of Hematopoietic Stem Cells and Protects the Stem Cell Pool during Regeneration.

    abstract::The transcription factor hepatic leukemia factor (HLF) is strongly expressed in hematopoietic stem cells (HSCs) and is thought to influence both HSC self-renewal and leukemogenesis. However, the physiological role of HLF in hematopoiesis and HSC function is unclear. Here, we report that mice lacking Hlf are viable wit...

    journal_title:Cell reports

    pub_type: 杂志文章

    doi:10.1016/j.celrep.2017.11.084

    authors: Komorowska K,Doyle A,Wahlestedt M,Subramaniam A,Debnath S,Chen J,Soneji S,Van Handel B,Mikkola HKA,Miharada K,Bryder D,Larsson J,Magnusson M

    更新日期:2017-12-19 00:00:00

  • SMUG1 Promotes Telomere Maintenance through Telomerase RNA Processing.

    abstract::Telomerase biogenesis is a complex process where several steps remain poorly understood. Single-strand-selective uracil-DNA glycosylase (SMUG1) associates with the DKC1-containing H/ACA ribonucleoprotein complex, which is essential for telomerase biogenesis. Herein, we show that SMUG1 interacts with the telomeric RNA ...

    journal_title:Cell reports

    pub_type: 杂志文章

    doi:10.1016/j.celrep.2019.07.040

    authors: Kroustallaki P,Lirussi L,Carracedo S,You P,Esbensen QY,Götz A,Jobert L,Alsøe L,Sætrom P,Gagos S,Nilsen H

    更新日期:2019-08-13 00:00:00

  • A polymorphic enhancer near GREM1 influences bowel cancer risk through differential CDX2 and TCF7L2 binding.

    abstract::A rare germline duplication upstream of the bone morphogenetic protein antagonist GREM1 causes a Mendelian-dominant predisposition to colorectal cancer (CRC). The underlying disease mechanism is strong, ectopic GREM1 overexpression in the intestinal epithelium. Here, we confirm that a common GREM1 polymorphism, rs1696...

    journal_title:Cell reports

    pub_type: 杂志文章

    doi:10.1016/j.celrep.2014.07.020

    authors: Lewis A,Freeman-Mills L,de la Calle-Mustienes E,Giráldez-Pérez RM,Davis H,Jaeger E,Becker M,Hubner NC,Nguyen LN,Zeron-Medina J,Bond G,Stunnenberg HG,Carvajal JJ,Gomez-Skarmeta JL,Leedham S,Tomlinson I

    更新日期:2014-08-21 00:00:00

  • GATA Factor-Dependent Positive-Feedback Circuit in Acute Myeloid Leukemia Cells.

    abstract::The master regulatory transcription factor GATA-2 triggers hematopoietic stem and progenitor cell generation. GATA2 haploinsufficiency is implicated in myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML), and GATA2 overexpression portends a poor prognosis for AML. However, the constituents of the GATA-2-de...

    journal_title:Cell reports

    pub_type: 杂志文章

    doi:10.1016/j.celrep.2016.07.058

    authors: Katsumura KR,Ong IM,DeVilbiss AW,Sanalkumar R,Bresnick EH

    更新日期:2016-08-30 00:00:00

  • Sub-minute Phosphoregulation of Cell Cycle Systems during Plasmodium Gamete Formation.

    abstract::The transmission of malaria parasites to mosquitoes relies on the rapid induction of sexual reproduction upon their ingestion into a blood meal. Haploid female and male gametocytes become activated and emerge from their host cells, and the males enter the cell cycle to produce eight microgametes. The synchronized natu...

    journal_title:Cell reports

    pub_type: 杂志文章

    doi:10.1016/j.celrep.2017.10.071

    authors: Invergo BM,Brochet M,Yu L,Choudhary J,Beltrao P,Billker O

    更新日期:2017-11-14 00:00:00

  • Vitamin D Receptor Controls Cell Stemness in Acute Myeloid Leukemia and in Normal Bone Marrow.

    abstract::Vitamin D (VD) is a known differentiating agent, but the role of VD receptor (VDR) is still incompletely described in acute myeloid leukemia (AML), whose treatment is based mostly on antimitotic chemotherapy. Here, we present an unexpected role of VDR in normal hematopoiesis and in leukemogenesis. Limited VDR expressi...

    journal_title:Cell reports

    pub_type: 杂志文章

    doi:10.1016/j.celrep.2019.12.055

    authors: Paubelle E,Zylbersztejn F,Maciel TT,Carvalho C,Mupo A,Cheok M,Lieben L,Sujobert P,Decroocq J,Yokoyama A,Asnafi V,Macintyre E,Tamburini J,Bardet V,Castaigne S,Preudhomme C,Dombret H,Carmeliet G,Bouscary D,Ginzburg YZ

    更新日期:2020-01-21 00:00:00

  • Presenilin deficiency or lysosomal inhibition enhances Wnt signaling through relocalization of GSK3 to the late-endosomal compartment.

    abstract::Sustained canonical Wnt signaling requires the inhibition of glycogen synthase kinase 3 (GSK3) activity by sequestration of GSK3 inside multivesicular endosomes (MVEs). Here, we show that Wnt signaling is increased by the lysosomal inhibitor chloroquine, which causes accumulation of MVEs. A similar MVE expansion and i...

    journal_title:Cell reports

    pub_type: 杂志文章

    doi:10.1016/j.celrep.2012.09.026

    authors: Dobrowolski R,Vick P,Ploper D,Gumper I,Snitkin H,Sabatini DD,De Robertis EM

    更新日期:2012-11-29 00:00:00

  • Inferring Active Metabolic Pathways from Proteomics and Essentiality Data.

    abstract::Here, we propose an approach to identify active metabolic pathways by integrating gene essentiality analysis and protein abundance. We use two bacterial species (Mycoplasma pneumoniae and Mycoplasma agalactiae) that share a high gene content similarity yet show significant metabolic differences. First, we build detail...

    journal_title:Cell reports

    pub_type: 杂志文章

    doi:10.1016/j.celrep.2020.107722

    authors: Montero-Blay A,Piñero-Lambea C,Miravet-Verde S,Lluch-Senar M,Serrano L

    更新日期:2020-06-02 00:00:00

  • Hidden Structural Modules in a Cooperative RNA Folding Transition.

    abstract::Large-scale, cooperative rearrangements underlie the functions of RNA in RNA-protein machines and gene regulation. To understand how such rearrangements are orchestrated, we used high-throughput chemical footprinting to dissect a seemingly concerted rearrangement in P5abc RNA, a paradigm of RNA folding studies. With m...

    journal_title:Cell reports

    pub_type: 杂志文章

    doi:10.1016/j.celrep.2018.02.101

    authors: Gracia B,Al-Hashimi HM,Bisaria N,Das R,Herschlag D,Russell R

    更新日期:2018-03-20 00:00:00