Bursty gene expression in the intact mammalian liver.

Abstract:

:Bursts of nascent mRNA have been shown to lead to substantial cell-cell variation in unicellular organisms, facilitating diverse responses to environmental challenges. It is unknown whether similar bursts and gene-expression noise occur in mammalian tissues. To address this, we combine single molecule transcript counting with dual-color labeling and quantification of nascent mRNA to characterize promoter states, transcription rates, and transcript lifetimes in the intact mouse liver. We find that liver gene expression is highly bursty, with promoters stochastically switching between transcriptionally active and inactive states. Promoters of genes with short mRNA lifetimes are active longer, facilitating rapid response while reducing burst-associated noise. Moreover, polyploid hepatocytes exhibit less noise than diploid hepatocytes, suggesting a possible benefit to liver polyploidy. Thus, temporal averaging and liver polyploidy dampen the intrinsic variability associated with transcriptional bursts. Our approach can be used to study transcriptional bursting in diverse mammalian tissues.

journal_name

Mol Cell

journal_title

Molecular cell

authors

Bahar Halpern K,Tanami S,Landen S,Chapal M,Szlak L,Hutzler A,Nizhberg A,Itzkovitz S

doi

10.1016/j.molcel.2015.01.027

subject

Has Abstract

pub_date

2015-04-02 00:00:00

pages

147-56

issue

1

eissn

1097-2765

issn

1097-4164

pii

S1097-2765(15)00050-7

journal_volume

58

pub_type

杂志文章
  • RNA editing-associated protein 1 is an RNA binding protein with specificity for preedited mRNA.

    abstract::RNA editing in the mitochondria of kinetoplastids involves the addition and deletion of uridines at specific sites as directed by guide RNAs (gRNAs). Ample evidence shows that ribonucleoprotein (RNP) complexes carry out this posttranscriptional processing. One component of RNA editing complexes is REAP-1, a protein of...

    journal_title:Molecular cell

    pub_type: 杂志文章

    doi:10.1016/s1097-2765(01)00231-3

    authors: Madison-Antenucci S,Hajduk SL

    更新日期:2001-04-01 00:00:00

  • The stress-induced MAP kinase p38 regulates endocytic trafficking via the GDI:Rab5 complex.

    abstract::Early endocytic membrane traffic is regulated by the small GTPase Rab5, which cycles between GTP- and GDP-bound states as well as between membrane and cytosol. The latter cycle depends on GDI, which functions as a Rab vehicle in the aqueous environment of the cytosol. Here, we report that formation of the GDI:Rab5 com...

    journal_title:Molecular cell

    pub_type: 杂志文章

    doi:10.1016/s1097-2765(01)00189-7

    authors: Cavalli V,Vilbois F,Corti M,Marcote MJ,Tamura K,Karin M,Arkinstall S,Gruenberg J

    更新日期:2001-02-01 00:00:00

  • Genome and Epigenome Maintenance by Keeping Histone Turnover in Check.

    abstract::In this issue of Molecular Cell, Taneja et al. (2017) uncover a dual role for the conserved chromatin remodeler Fft3 in the maintenance of silent heterochromatin and the suppression of replication barriers at euchromatic loci through controlled histone turnover. ...

    journal_title:Molecular cell

    pub_type: 杂志文章

    doi:10.1016/j.molcel.2017.03.015

    authors: Fortuny A,Polo SE

    更新日期:2017-04-06 00:00:00

  • Hematopoietic Signaling Mechanism Revealed from a Stem/Progenitor Cell Cistrome.

    abstract::Thousands of cis-elements in genomes are predicted to have vital functions. Although conservation, activity in surrogate assays, polymorphisms, and disease mutations provide functional clues, deletion from endogenous loci constitutes the gold-standard test. A GATA-2-binding, Gata2 intronic cis-element (+9.5) required ...

    journal_title:Molecular cell

    pub_type: 杂志文章

    doi:10.1016/j.molcel.2015.05.020

    authors: Hewitt KJ,Kim DH,Devadas P,Prathibha R,Zuo C,Sanalkumar R,Johnson KD,Kang YA,Kim JS,Dewey CN,Keles S,Bresnick EH

    更新日期:2015-07-02 00:00:00

  • Insights into the regulatory mechanism for caspase-8 activation.

    abstract::In the death receptor induced apoptotic pathway, caspase-8 autocatalytically cleaves itself at specific cleavage sites. To better understand the regulatory mechanisms behind caspase-8 activation, we compared active wild-type caspase-8 (wtC8) and an uncleavable form of procaspase-8 (uncleavable C8). We demonstrate that...

    journal_title:Molecular cell

    pub_type: 杂志文章

    doi:10.1016/s1097-2765(03)00059-5

    authors: Donepudi M,Mac Sweeney A,Briand C,Grütter MG

    更新日期:2003-02-01 00:00:00

  • Localization of the ribosomal protection protein Tet(O) on the ribosome and the mechanism of tetracycline resistance.

    abstract::Tet(O) belongs to a class of ribosomal protection proteins that mediate tetracycline resistance. It is a G protein that shows significant sequence similarity to elongation factor EF-G. Here we present a cryo-electron microscopic reconstruction, at 16 A resolution, of its complex with the E. coli 70S ribosome. Tet(O) w...

    journal_title:Molecular cell

    pub_type: 杂志文章

    doi:10.1016/s1097-2765(01)00238-6

    authors: Spahn CM,Blaha G,Agrawal RK,Penczek P,Grassucci RA,Trieber CA,Connell SR,Taylor DE,Nierhaus KH,Frank J

    更新日期:2001-05-01 00:00:00

  • Blast from the Past: Reassessing Forgotten Translation Inhibitors, Antibiotic Selectivity, and Resistance Mechanisms to Aid Drug Development.

    abstract::Protein synthesis is a major target within the bacterial cell for antibiotics. Investigations into ribosome-targeting antibiotics have provided much needed functional and structural insight into their mechanism of action. However, the increasing prevalence of multi-drug-resistant bacteria has limited the utility of ou...

    journal_title:Molecular cell

    pub_type: 杂志文章,评审

    doi:10.1016/j.molcel.2015.10.019

    authors: Arenz S,Wilson DN

    更新日期:2016-01-07 00:00:00

  • Yng1 PHD finger binding to H3 trimethylated at K4 promotes NuA3 HAT activity at K14 of H3 and transcription at a subset of targeted ORFs.

    abstract::Posttranslational histone modifications participate in modulating the structure and function of chromatin. Promoters of transcribed genes are enriched with K4 trimethylation and hyperacetylation on the N-terminal tail of histone H3. Recently, PHD finger proteins, like Yng1 in the NuA3 HAT complex, were shown to intera...

    journal_title:Molecular cell

    pub_type: 杂志文章

    doi:10.1016/j.molcel.2006.10.026

    authors: Taverna SD,Ilin S,Rogers RS,Tanny JC,Lavender H,Li H,Baker L,Boyle J,Blair LP,Chait BT,Patel DJ,Aitchison JD,Tackett AJ,Allis CD

    更新日期:2006-12-08 00:00:00

  • Hsp70- and Hsp90-Mediated Regulation of the Conformation of p53 DNA Binding Domain and p53 Cancer Variants.

    abstract::The activity of the tumor suppressor p53 has to be timed and balanced closely to prevent untimely induction of cell death. The stability of p53 depends on the ubiquitin ligase Mdm2 but also on Hsp70 and Hsp90 chaperones that interact with its DNA binding domain (DBD). Using hydrogen exchange mass spectrometry and bioc...

    journal_title:Molecular cell

    pub_type: 杂志文章

    doi:10.1016/j.molcel.2019.03.032

    authors: Boysen M,Kityk R,Mayer MP

    更新日期:2019-05-16 00:00:00

  • Chromatin opening of DNA satellites by targeted sequence-specific drugs.

    abstract::There are few tools available for dissecting and elucidating the functions of DNA satellites and other nongenic DNA. To address this, we have explored the experimental potential of DNA sequence-specific drugs containing pyrrole and imidazole amino acids (polyamides). Compounds were synthesized that target different Dr...

    journal_title:Molecular cell

    pub_type: 杂志文章

    doi:10.1016/s1097-2765(00)00099-x

    authors: Janssen S,Durussel T,Laemmli UK

    更新日期:2000-11-01 00:00:00

  • Extracellular adenosine sensing-a metabolic cell death priming mechanism downstream of p53.

    abstract::Tumor cells undergo changes in metabolism to meet their energetic and anabolic needs. It is conceivable that mechanisms exist to sense these changes and link them to pathways that eradicate cells primed for cancer development. We report that the tumor suppressor p53 activates a cell death priming mechanism that senses...

    journal_title:Molecular cell

    pub_type: 杂志文章

    doi:10.1016/j.molcel.2013.03.016

    authors: Long JS,Crighton D,O'Prey J,Mackay G,Zheng L,Palmer TM,Gottlieb E,Ryan KM

    更新日期:2013-05-09 00:00:00

  • Isoform Switch of TET1 Regulates DNA Demethylation and Mouse Development.

    abstract::The methylcytosine oxidase TET proteins play important roles in DNA demethylation and development. However, it remains elusive how exactly they target substrates and execute oxidation. Interestingly, we found that, in mice, the full-length TET1 isoform (TET1e) is restricted to early embryos, embryonic stem cells (ESCs...

    journal_title:Molecular cell

    pub_type: 杂志文章

    doi:10.1016/j.molcel.2016.10.030

    authors: Zhang W,Xia W,Wang Q,Towers AJ,Chen J,Gao R,Zhang Y,Yen CA,Lee AY,Li Y,Zhou C,Liu K,Zhang J,Gu TP,Chen X,Chang Z,Leung D,Gao S,Jiang YH,Xie W

    更新日期:2016-12-15 00:00:00

  • The BCL-2 family reunion.

    abstract::B cell CLL/lymphoma-2 (BCL-2) and its relatives comprise the BCL-2 family of proteins, which were originally characterized with respect to their roles in controlling outer mitochondrial membrane integrity and apoptosis. Current observations expand BCL-2 family function to include numerous cellular pathways. Here we wi...

    journal_title:Molecular cell

    pub_type: 杂志文章,评审

    doi:10.1016/j.molcel.2010.01.025

    authors: Chipuk JE,Moldoveanu T,Llambi F,Parsons MJ,Green DR

    更新日期:2010-02-12 00:00:00

  • Linking differential chromatin loops to transcriptional decisions.

    abstract::GATA-1 and GATA-2 control proliferation and differentiation of hematopoietic progenitor cells via transcriptional regulation. In this issue of Molecular Cell, Jing et al. (2008) demonstrate that GATA factor exchange on the Kit locus directs a transcriptional switch by reconfiguring chromatin loops. ...

    journal_title:Molecular cell

    pub_type: 评论,杂志文章

    doi:10.1016/j.molcel.2008.01.008

    authors: Apostolou E,Thanos D

    更新日期:2008-02-01 00:00:00

  • Rad54 functions as a heteroduplex DNA pump modulated by its DNA substrates and Rad51 during D loop formation.

    abstract::The displacement loop (D loop) is the product of homology search and DNA strand invasion, constituting a central intermediate in homologous recombination (HR). In eukaryotes, the Rad51 DNA strand exchange protein is assisted in D loop formation by the Rad54 motor protein. Curiously, Rad54 also disrupts D loops. How th...

    journal_title:Molecular cell

    pub_type: 杂志文章

    doi:10.1016/j.molcel.2013.12.027

    authors: Wright WD,Heyer WD

    更新日期:2014-02-06 00:00:00

  • Molecular structures of crossover and noncrossover intermediates during gap repair in yeast: implications for recombination.

    abstract::The molecular structures of crossover (CO) and noncrossover (NCO) intermediates were determined by sequencing the products formed when a gapped plasmid was repaired using a diverged chromosomal template. Analyses were done in the absence of mismatch repair (MMR) to allow efficient detection of strand-transfer intermed...

    journal_title:Molecular cell

    pub_type: 杂志文章

    doi:10.1016/j.molcel.2010.02.028

    authors: Mitchel K,Zhang H,Welz-Voegele C,Jinks-Robertson S

    更新日期:2010-04-23 00:00:00

  • Spt6 Association with RNA Polymerase II Directs mRNA Turnover During Transcription.

    abstract::Spt6 is an essential histone chaperone that mediates nucleosome reassembly during gene transcription. Spt6 also associates with RNA polymerase II (RNAPII) via a tandem Src2 homology domain. However, the significance of Spt6-RNAPII interaction is not well understood. Here, we show that Spt6 recruitment to genes and the...

    journal_title:Molecular cell

    pub_type: 杂志文章

    doi:10.1016/j.molcel.2018.05.020

    authors: Dronamraju R,Hepperla AJ,Shibata Y,Adams AT,Magnuson T,Davis IJ,Strahl BD

    更新日期:2018-06-21 00:00:00

  • Mitophagy Controls the Activities of Tumor Suppressor p53 to Regulate Hepatic Cancer Stem Cells.

    abstract::Autophagy is required for benign hepatic tumors to progress into malignant hepatocellular carcinoma. However, the mechanism is unclear. Here, we report that mitophagy, the selective removal of mitochondria by autophagy, positively regulates hepatic cancer stem cells (CSCs) by suppressing the tumor suppressor p53. When...

    journal_title:Molecular cell

    pub_type: 杂志文章

    doi:10.1016/j.molcel.2017.09.022

    authors: Liu K,Lee J,Kim JY,Wang L,Tian Y,Chan ST,Cho C,Machida K,Chen D,Ou JJ

    更新日期:2017-10-19 00:00:00

  • The Sjögren-Larsson syndrome gene encodes a hexadecenal dehydrogenase of the sphingosine 1-phosphate degradation pathway.

    abstract::Sphingosine 1-phosphate (S1P) functions not only as a bioactive lipid molecule, but also as an important intermediate of the sole sphingolipid-to-glycerolipid metabolic pathway. However, the precise reactions and the enzymes involved in this pathway remain unresolved. We report here that yeast HFD1 and the Sjögren-Lar...

    journal_title:Molecular cell

    pub_type: 杂志文章

    doi:10.1016/j.molcel.2012.04.033

    authors: Nakahara K,Ohkuni A,Kitamura T,Abe K,Naganuma T,Ohno Y,Zoeller RA,Kihara A

    更新日期:2012-05-25 00:00:00

  • Recognition of Lys48-Linked Di-ubiquitin and Deubiquitinating Activities of the SARS Coronavirus Papain-like Protease.

    abstract::Deubiquitinating enzymes (DUBs) recognize and cleave linkage-specific polyubiquitin (polyUb) chains, but mechanisms underlying specificity remain elusive in many cases. The severe acute respiratory syndrome (SARS) coronavirus papain-like protease (PLpro) is a DUB that cleaves ISG15, a two-domain Ub-like protein, and L...

    journal_title:Molecular cell

    pub_type: 杂志文章

    doi:10.1016/j.molcel.2016.04.016

    authors: Békés M,van der Heden van Noort GJ,Ekkebus R,Ovaa H,Huang TT,Lima CD

    更新日期:2016-05-19 00:00:00

  • Imprinted Small RNAs Unraveled: Maternal MicroRNAs Antagonize a Paternal-Genome-Driven Gene Expression Network.

    abstract::Whipple et al., 2020 describe that, in neurons, a dense cluster of maternally expressed microRNAs post-transcriptionally downregulates several imprinted genes expressed from the paternal genome-an antagonistic mechanism that modulates neuronal functions and provides insights into the evolution of genomic imprinting. ...

    journal_title:Molecular cell

    pub_type: 评论,杂志文章

    doi:10.1016/j.molcel.2020.03.019

    authors: Ghousein A,Feil R

    更新日期:2020-04-02 00:00:00

  • A Multiplexed Assay for Exon Recognition Reveals that an Unappreciated Fraction of Rare Genetic Variants Cause Large-Effect Splicing Disruptions.

    abstract::Mutations that lead to splicing defects can have severe consequences on gene function and cause disease. Here, we explore how human genetic variation affects exon recognition by developing a multiplexed functional assay of splicing using Sort-seq (MFASS). We assayed 27,733 variants in the Exome Aggregation Consortium ...

    journal_title:Molecular cell

    pub_type: 杂志文章

    doi:10.1016/j.molcel.2018.10.037

    authors: Cheung R,Insigne KD,Yao D,Burghard CP,Wang J,Hsiao YE,Jones EM,Goodman DB,Xiao X,Kosuri S

    更新日期:2019-01-03 00:00:00

  • Arginine methylation modulates autophagic degradation of PGL granules in C. elegans.

    abstract::The selective degradation of intracellular components by autophagy involves sequential interactions of the cargo with a receptor, which also binds the autophagosomal protein Atg8 and a scaffold protein. Here, we demonstrated that mutations in C. elegans epg-11, which encodes an arginine methyltransferase homologous to...

    journal_title:Molecular cell

    pub_type: 杂志文章

    doi:10.1016/j.molcel.2013.09.014

    authors: Li S,Yang P,Tian E,Zhang H

    更新日期:2013-11-07 00:00:00

  • Uncoupling of sister replisomes during eukaryotic DNA replication.

    abstract::The duplication of eukaryotic genomes involves the replication of DNA from multiple origins of replication. In S phase, two sister replisomes assemble at each active origin, and they replicate DNA in opposite directions. Little is known about the functional relationship between sister replisomes. Some data imply that ...

    journal_title:Molecular cell

    pub_type: 杂志文章

    doi:10.1016/j.molcel.2010.11.027

    authors: Yardimci H,Loveland AB,Habuchi S,van Oijen AM,Walter JC

    更新日期:2010-12-10 00:00:00

  • ChIC and ChEC; genomic mapping of chromatin proteins.

    abstract::To map the genomic interaction sites of chromatin proteins, two related methods were developed and experimentally explored in Saccharomyces cerevisiae. The ChIC method (chromatin immunocleavage) consists of tethering a fusion protein (pA-MN) consisting of micrococcal nuclease (MN) and staphylococcal protein A to speci...

    journal_title:Molecular cell

    pub_type: 杂志文章

    doi:10.1016/j.molcel.2004.09.007

    authors: Schmid M,Durussel T,Laemmli UK

    更新日期:2004-10-08 00:00:00

  • Generating crossovers by resolution of nicked Holliday junctions: a role for Mus81-Eme1 in meiosis.

    abstract::The double Holliday junction (dHJ) is generally regarded to be a key intermediate of meiotic recombination, whose resolution is critical for the formation of crossover recombinants. In fission yeast, the Mus81-Eme1 endonuclease has been implicated in resolving dHJs. Consistent with this role, we show that Mus81-Eme1 i...

    journal_title:Molecular cell

    pub_type: 杂志文章

    doi:10.1016/s1097-2765(03)00343-5

    authors: Osman F,Dixon J,Doe CL,Whitby MC

    更新日期:2003-09-01 00:00:00

  • MicroRNAs cross the line: the battle for mRNA stability enters the coding sequence.

    abstract::A study in this issue of Molecular Cell (Elcheva et al., 2009) shows the inherent instability of the betaTrCP1 mRNA to be caused by microRNA-183 targeting the coding sequence; interestingly, this action is directly opposed by the RNA-binding protein CRD-BP. ...

    journal_title:Molecular cell

    pub_type: 评论,杂志文章

    doi:10.1016/j.molcel.2009.07.006

    authors: Nielsen AF,Gloggnitzer J,Martinez J

    更新日期:2009-07-31 00:00:00

  • Fluoxetine-resistant mutants in C. elegans define a novel family of transmembrane proteins.

    abstract::Fluoxetine (Prozac) is an antidepressant that is thought to act by blocking presynaptic reuptake of the neurotransmitter serotonin. Despite widespread clinical use of fluoxetine, direct evidence for this mechanism has been difficult to obtain in vivo. We have determined that fluoxetine has an additional neuromuscular ...

    journal_title:Molecular cell

    pub_type: 杂志文章

    doi:10.1016/s1097-2765(00)80362-7

    authors: Choy RK,Thomas JH

    更新日期:1999-08-01 00:00:00

  • Swi6/HP1 recruits a JmjC domain protein to facilitate transcription of heterochromatic repeats.

    abstract::Heterochromatin formation is generally thought to result in transcriptional repression of target loci. However, RNAi-mediated heterochromatin assembly requires RNA polymerase II (Pol II) transcription. The mechanism facilitating Pol II accessibility to heterochromatin is unknown. We show that the fission yeast Epe1, a...

    journal_title:Molecular cell

    pub_type: 杂志文章

    doi:10.1016/j.molcel.2006.05.010

    authors: Zofall M,Grewal SI

    更新日期:2006-06-09 00:00:00

  • Molecular Basis for Hormone Recognition and Activation of Corticotropin-Releasing Factor Receptors.

    abstract::Corticotropin-releasing factor (CRF) and the three related peptides urocortins 1-3 (UCN1-UCN3) are endocrine hormones that control the stress responses by activating CRF1R and CRF2R, two members of class B G-protein-coupled receptors (GPCRs). Here, we present two cryoelectron microscopy (cryo-EM) structures of UCN1-bo...

    journal_title:Molecular cell

    pub_type: 杂志文章

    doi:10.1016/j.molcel.2020.01.013

    authors: Ma S,Shen Q,Zhao LH,Mao C,Zhou XE,Shen DD,de Waal PW,Bi P,Li C,Jiang Y,Wang MW,Sexton PM,Wootten D,Melcher K,Zhang Y,Xu HE

    更新日期:2020-02-06 00:00:00