Dr. Lars Barquist

Integrative Informatik in der Infektionsbiologie

Unsere Forschung

Die Arbeitsgruppe von Lars Barquist entwickelt neue statistische und bioinformatische Ansätze zur Analyse und Visualisierung funktioneller Genomdaten. Die Forscher verbinden umfangreiche Sequenzierdaten mit modernen computergestützten Technologien, um neue Einblicke in die bakterielle Krankheitsentstehung zu gewinnen und RNA-basierte Therapieansätze zu entwickeln.

Die Entwicklung von Hochdurchsatztechnologien in der Infektionsbiologie erlaubt es, Tausende von genetischen Loci gleichzeitig in einem einzigen Experiment zu untersuchen. Dies hat zur Entstehung umfangreicher Datensätze zur Interaktion von Krankheitserregern und Wirt geführt. Um unser Verständnis von Krankheitserregern weiter zu verbessern, müssen wir nun Wege finden, diese vielfältigen Daten in Zusammenhang zu bringen und daraus Hypothesen abzuleiten.

Lars Barquist und sein Team entwickeln neuartige Methoden im Bereich Statistik, Bioinformatik und Visualisierung. Die Arbeitsgruppe wendet moderne Werkzeuge wie maschinelles Lernen und Bayessche Statistik an, um unser Verständnis von Krankheitserregern zu verbessern. Ihr Ziel ist es, den derzeitigen Engpass bei der Interpretation komplexer Daten zu überwinden.

Zusammen mit anderen Forschungsgruppen am HIRI hat die Gruppe an der Weiterentwicklung verschiedener zukunftsweisender Technologien gearbeitet, darunter CLIP-seq, Dual RNA-seq, CRISPRi-Screens, Transposon-Mutagenese und Meta-Transkriptomik. Ihr Ziel ist es, durch die Verschmelzung von Sequenzierdaten und computergestützten Technologien unser Verständnis der bakteriellen Krankheitsentstehung und die Entwicklung von RNA-basierten Behandlungsmethoden voran zu bringen.

Team-Mitglieder

Gruppenleiter

Postdoc

Postdoc

Gast

Forschungsprojekte

Überblick

Grafische Zusammenfassung der Forschungsarbeit im Barquist-Labor

Die Forschungsschwerpunkte der Arbeitsgruppe von Lars Barquist
Graphical abstract © Helmholtz-Institut Würzburg / Sandy Westermann

Die Arbeitsgruppe analysiert und integriert genomische und postgenomische Daten, um Einblick in die bakterielle Pathogenese zu gewinnen. Ihr Tätigkeitsschwerpunkt liegt in der Entwicklung bioinformatischer Techniken zur Analyse und Interpretation der Ergebnisse von Experimenten mit Hochdurchsatz-Sequenzierung einschließlich Transposon-Insertions-Sequenzierung, CLIP-seq und dual RNA-seq. Die Gruppe erarbeitet neue Algorithmen und statistische Ansätze für diese Arten von Daten, um Einblicke in die Wirt-Mikroben-Interaktionen und in die RNA-basierte Regulation in bakteriellen Pathogenen zu gewinnen.

Ein weiteres Arbeitsgebiet ist die Anwendung von Machine-Learning-Werkzeugen in Zusammenhang mit der Evolution bakterieller Pathogene unter Verwendung von Genomsequenzierungsdaten. Durch die Analyse der Architektur dieser Maschinen konnte die Arbeitsgruppe neue Erkenntnisse darüber gewinnen, wie sich Krankheitserreger an ihre Wirte anpassen. Aktuell wird untersucht, wie zusätzliche Informationsschichten in solche Modelle integriert werden können, z.B. Informationen zur Genexpression und Mutationen in nicht-kodierender RNA. So lässt sich ein umfassenderes Bild des Verhaltens von Krankheitserregern entwickeln.

Publikationen

2024

Expanding the flexibility of base editing for high-throughput genetic screens in bacteria

Gawlitt S, Collins SP, Yu Y, Blackman SA, Barquist L, Beisel CL (2024)

Nucleic Acids Research (Online ahead of print)

Improved RNA stability estimation through Bayesian modeling reveals most Salmonella transcripts have subminute half-lives

Jenniches L, Michaux C, Popella L, Reichardt S, Vogel J, Westermann AJ, Barquist L (2024)

Proceedings of the National Academy of Sciences of the United States of America 121 (14): e2308814121

An expanded transcriptome atlas for Bacteroides thetaiotaomicron reveals a small RNA that modulates tetracycline sensitivity

Ryan D, Bornet E, Prezza G, Alampalli SV, Franco de Carvalho T, Felchle H, Ebbecke T, Hayward RJ, Deutschbauer AM, Barquist L, Westermann AJ (2024)

Nature Microbiology 9 (4): 1130-1144

Improved prediction of bacterial CRISPRi guide efficiency from depletion screens through mixed-effect machine learning and data integration

Yu Y, Gawlitt S, de Andrade E Sousa LB, Merdivan E, Piraud M, Beisel CL, Barquist L (2024)

Genome Biology 25 (1): 13

A method to correct for local alterations in DNA copy number that bias functional genomics assays applied to antibiotic-treated bacteria

Sullivan GJ, Barquist L, Cain AK (2024)

mSystems 12: e0066523

2023

Vector-borne Trypanosoma brucei parasites develop in artificial human skin and persist as skin tissue forms

Reuter C, Hauf L, Imdahl F, Sen R, Vafadarnejad E, Fey P, Finger T, Jones NG, Walles H, Barquist L, …, Groeber-Becker F, Engstler M (2023)

Nature Communications 14 (1): 7660

Ribosome profiling reveals the fine-tuned response of Escherichia coli to mild and severe acid stress

Schumacher K, Gelhausen R, Kion-Crosby W, Barquist L, Backofen R, Jung K (2023)

mSystems 8 (6): e0103723

Grad-seq analysis of Enterococcus faecalis and Enterococcus faecium provides a global view of RNA and protein complexes in these two opportunistic pathogens

Michaux C, Gerovac M, Hansen EE, Barquist L, Vogel J (2023)

microLife 4: uqac027

DksA is a conserved master regulator of stress response in Acinetobacter baumannii

Maharjan RP, Sullivan GJ, Adams FG, Shah BS, Hawkey J, Delgado N, Semenec L, Dinh H, Li L, Short FL, …, Eijkelkamp BA, Cain AK (2023)

Nucleic Acids Research 51 (12): 6101-6119

Improved Bacterial Single-Cell RNA-Seq through Automated MATQ-Seq and Cas9-Based Removal of rRNA Reads

Homberger C, Hayward RJ, Barquist L, Vogel J (2023)

mBio 14 (2): e0355722

Design and off-target prediction for antisense oligomers targeting bacterial mRNAs with the MASON webserver

Jung JJ, Popella L, Do PT, Pfau P, Vogel J, Barquist L (2023)

RNA 299 (5): 570-583

2022

Network community detection and clustering with random walks

Ballal A, Kion-Crosby W, Morozov A (2022)

Physical Review Research 4 (4): 583

A target expression threshold dictates invader defense and prevents autoimmunity by CRISPR-Cas13

Vialetto E, Yu Y, Collins SP, Wandera KG, Barquist L, Beisel CL (2022)

Cell Host & Microbe 3128 (22): 00273-6

Comprehensive analysis of PNA-based antisense antibiotics targeting various essential genes in uropathogenic Escherichia coli

Popella L, Jung J, Do PT, Hayward RJ, Barquist L, Vogel J (2022)

Nucleic Acids Research 50 (11): 6435–6452

Ushering in a new era of single-cell transcriptomics in bacteria

Homberger C, Barquist L, Vogel J (2022)

microLife 3: uqac020

Cellular RNA Targets of Cold Shock Proteins CspC and CspE and Their Importance for Serum Resistance in Septicemic Escherichia coli

Yair Y, Michaux C, Biran D, Bernhard J, Vogel J, Barquist L, Ron EZ (2022)

mSystems 7 (4): e0008622

Comparative genomics provides structural and functional insights into Bacteroides RNA biology

Prezza G, Ryan D, Mädler G, Reichardt S, Barquist L, Westermann AJ (2022)

Molecular Microbiology 117 (1): 67-85

2021

RNA landscape of the emerging cancer-associated microbe Fusobacterium nucleatum

Ponath F, Tawk C, Zhu Y, Barquist L, Faber F, Vogel J (2021)

Nature Microbiology 6 (8): 1007-1020

Noncanonical crRNAs derived from host transcripts enable multiplexable RNA detection by Cas9

Jiao C, Sharma S, Dugar G, Peeck NL, Bischler T, Wimmer F, Yu Y, Barquist L, Schoen C, Kurzai O, Sharma CM, Beisel CL (2021)

Science 372 (6545): 941-948

Global RNA profiles show target selectivity and physiological effects of peptide-delivered antisense antibiotics

Popella L, Jung J, Popova K, Ðurica-Mitic S, Barquist L, Vogel J (2021)

Nucleic Acids Research 49 (8): 4705-4724

Common Features in lncRNA Annotation and Classification: A Survey

Klapproth C, Sen R, Stadler PF, Findeiß S, Fallmann J (2021)

Non-coding RNA 7 (4): 77

An RNA-centric global view of Clostridioides difficile reveals broad activity of Hfq in a clinically important gram-positive bacterium

Fuchs M, Lamm-Schmidt V, Sulzer J, Ponath F, Jenniches L, Kirk JA, Fagan RP, Barquist L, Vogel J, Faber F (2021)

PNAS 118 (25): e2103579118

Functional analysis of colonization factor antigen I positive enterotoxigenic Escherichia coli identifies genes implicated in survival in water and host colonization

Abd El Ghany M, Barquist L, Clare S, Brandt C, Mayho M, Joffre E, Sjöling Å, Turner AK, Klena JD, Kingsley RA, …, Dougan G, Pickard D (2021)

Microbial Genomics 7 (6): 000554

Global identification of RsmA/N binding sites in Pseudomonas aeruginosa by in vivo UV CLIP-seq

Chihara K, Barquist L, Takasugi K, Noda N, Tsuneda S (2021)

RNA Biology 18 (12): 2401-2416

Global identification of RsmA/N binding sites in Pseudomonas aeruginosa by in vivo UV CLIP-seq

Chihara K, Barquist L, Takasugi K, Noda N, Tsuneda S (2021)

RNA Biology 18 (12): 2401-2416

2020

A high-resolution transcriptome map identifies small RNA regulation of metabolism in the gut microbe Bacteroides thetaiotaomicron

Ryan D, Jenniches L, Reichardt S, Barquist L, Westermann AJ (2020)

Nature Communications 11 (1): 3557

Dual RNA-seq of Orientia tsutsugamushi informs on host-pathogen interactions for this neglected intracellular human pathogen

Mika-Gospodorz B, Giengkam S, Westermann AJ, Wongsantichon J, Kion-Crosby W, Chuenklin S, Wang LC, Sunyakumthorn P, Sobota RM, Subbian S, …, Barquist L, Salje J (2020)

Nature Communications 11: 3363

An amphipathic peptide with antibiotic activity against multidrug-resistant Gram-negative bacteria

Elliott AG, Huang JX, Neve S, Zuegg J, Edwards IA, Cain AK, Boinett CJ, Barquist L, Lundberg CV, Steen J, …, Strandh M, Cooper MA (2020)

Nature Communications 11: 3184

A decade of advances in transposon-insertion sequencing

Cain AK, Barquist L, Goodman AL, Paulsen IT, Parkhill J, van Opijnen T (2020)

Nature Reviews Genetics 21 (9): 526-540

The minimal meningococcal ProQ protein has an intrinsic capacity for structure-based global RNA recognition

Bauriedl S, Gerovac M, Heidrich N, Bischler T, Barquist L, Vogel J, Schoen C (2020)

Nature Communications 11: 2823

A global data-driven census of Salmonella small proteins and their potential functions in bacterial virulence

Venturini E, Svensson SL, Maaß S, Gelhausen R, Eggenhofer F, Li L, Cain AK, Parkhill J, Becher D, Backofen R, …, Westermann AJ, Vogel J (2020)

microLife 1 (1): 597

Single-Nucleotide RNA Maps for the Two Major Nosocomial Pathogens Enterococcus faecalis and Enterococcus faecium

Michaux C, Hansen EE, Jenniches L, Gerovac M, Barquist L, Vogel J (2020)

Frontiers in Cellular and Infection Microbiology 10: 600325

Whole genome sequencing of Thametopoea pityocampa revealed putative pesticide targets

Shahraki A, Yu Y, Gul ZM, Liang C, Iyison NB (2020)

Genomics 112 (6): 4203-4207

Global discovery of bacterial RNA-binding proteins by RNase-sensitive gradient profiles reports a new FinO domain protein

Gerovac M, El Mouali Y, Kuper J, Kisker C, Barquist L, Vogel J (2020)

RNA 26 (10): 1448-1463

Plugging Small RNAs into the Network

Barquist L (2020)

mSystems 5 (3): e00422-20

2019

Conditional Hfq Association with Small Noncoding RNAs in Pseudomonas aeruginosa Revealed through Comparative UV Cross-Linking Immunoprecipitation Followed by High-Throughput Sequencing

Chihara K, Bischler T, Barquist L, Monzon VA, Noda N, Vogel J, Tsuneda S (2019)

mSystems 4 (6): e00590-19

Rapid transcriptional responses to serum exposure are associated with sensitivity and resistance to antibody-mediated complement killing in invasive Salmonella Typhimurium ST313

Ondari EM, Klemm EJ, Msefula CL, El Ghany MA, Heath JN, Pickard DJ, Barquist L, Dougan G, Kingsley RA, MacLennan CA (2019)

Wellcome Open Research 4: 74

Transcriptional noise and exaptation as sources for bacterial sRNAs

Jose BR, Gardner PP, Barquist L (2019)

Biochemical Society Transactions 47 (2): 527-539

2018

Global Maps of ProQ Binding In Vivo Reveal Target Recognition via RNA Structure and Stability Control at mRNA 3' Ends

Holmqvist E, Li L, Bischler T, Barquist L, Vogel J (2018)

Molecular Cell 70 (5): 971-982.e6

A global genomic approach uncovers novel components for twitching motility-mediated biofilm expansion in Pseudomonas aeruginosa

Nolan LM, Whitchurch CB, Barquist L, Katrib M, Boinett CJ, Mayho M, Goulding D, Charles IG, Filloux A, Parkhill J, Cain AK (2018)

Microbial Genomics 4 (11): e000229

Functional analysis of Salmonella Typhi adaptation to survival in water

Kingsley RA, Langridge G, Smith SE, Makendi C, Fookes M, Wileman TM, El Ghany MA, Keith Turner A, Dyson ZA, Sridhar S, …, Barquist L, Dougan G (2018)

Environmental Microbiology 20 (11): 4079-4090

Morphological, genomic and transcriptomic responses of Klebsiella pneumoniae to the last-line antibiotic colistin

Cain AK, Boinett CJ, Barquist L, Dordel J, Fookes M, Mayho M, Ellington MJ, Goulding D, Pickard D, Wick RR, …, Parkhill J, Thomson NR (2018)

Scientific Reports 8 (1): 9868

Machine learning identifies signatures of host adaptation in the bacterial pathogen Salmonella enterica

Wheeler NE, Gardner PP, Barquist L (2018)

PLOS Genetics 14 (5): e1007333

2017

The primary transcriptome of Neisseria meningitidis and its interaction with the RNA chaperone Hfq

Heidrich N, Bauriedl S, Barquist L, Li L, Schoen C, Vogel J (2017)

Nucleic Acids Research 45 (10): 6147-6167

RNA target profiles direct the discovery of virulence functions for the cold-shock proteins CspC and CspE

Michaux C, Holmqvist E, Vasicek E, Sharan M, Barquist L, Westermann AJ, Gunn JS, Vogel J (2017)

PNAS 114 (26): 6824-6829

Role of sapA and yfgA in Susceptibility to Antibody-Mediated Complement-Dependent Killing and Virulence of Salmonella enterica Serovar Typhimurium

Ondari EM, Heath JN, Klemm EJ, Langridge G, Barquist L, Goulding DA, Clare S, Dougan G, Kingsley RA, MacLennan CA (2017)

Infection and Immunity 85 (9): pii: e00419-17

Resolving host-pathogen interactions by dual RNA-seq

Westermann AJ, Barquist L, Vogel J (2017)

PLOS Pathogens 13 (2): e1006033

2016

Distinct Salmonella Enteritidis lineages associated with enterocolitis in high-income settings and invasive disease in low-income settings

Feasey NA, Hadfield J, Keddy KH, Dallman TJ, Jacobs J, Deng X, Wigley P, Barquist L, Langridge GC, Feltwell T, …, Gordon MA, Thomson NR (2016)

Nature Genetics 48 (10): 1211-1217

Dual RNA-seq unveils noncoding RNA functions in host-pathogen interactions

Westermann AJ, Forstner KU, Amman F, Barquist L, Chao Y, Schulte LN, Muller L, Reinhardt R, Stadler PF, Vogel J (2016)

Nature 529 (7587): 496-501

Global RNA recognition patterns of post-transcriptional regulators Hfq and CsrA revealed by UV crosslinking in vivo

Holmqvist E, Wright PR, Li L, Bischler T, Barquist L, Reinhardt R, Backofen R, Vogel J (2016)

The EMBO Journal 35 (9): 991-1011

The TraDIS toolkit: sequencing and analysis for dense transposon mutant libraries

Barquist L, Mayho M, Cummins C, Cain AK, Boinett CJ, Page AJ, Langridge GC, Quail MA, Keane JA, Parkhill J (2016)

Bioinformatics 32 (7): 1109-11

Studying RNA Homology and Conservation with Infernal: From Single Sequences to RNA Families

Barquist L, Burge SW, Gardner PP (2016)

Current Protocols in Bioinformatics 54: 12.13.1-12.13.25

Molecular phenotyping of infection-associated small non-coding RNAs

Barquist L, Westermann AJ, Vogel J (2016)

Philosophical Transactions of the Royal Society of London B: Biological Sciences 371 (1707): 20160081

The in vitro and in vivo effects of constitutive light expression on a bioluminescent strain of the mouse enteropathogen Citrobacter rodentium

Read HM, Mills G, Johnson S, Tsai P, Dalton J, Barquist L, Print CG, Patrick WM, Wiles S (2016)

PeerJ 4: e2130

A profile-based method for identifying functional divergence of orthologous genes in bacterial genomes

Wheeler NE, Barquist L, Kingsley RA, Gardner PP (2016)

Bioinformatics 32 (23): 3566-3574

2015

Accelerating Discovery and Functional Analysis of Small RNAs with New Technologies

Barquist L, Vogel J (2015)

Annual Review of Genetics 49: 367-94

High-throughput analysis of gene essentiality and sporulation in Clostridium difficile

Dembek M, Barquist L, Boinett CJ, Cain AK, Mayho M, Lawley TD, Fairweather NF, Fagan RP (2015)

mBio 6 (2): e02383

Patterns of genome evolution that have accompanied host adaptation in Salmonella

Langridge GC, Fookes M, Connor TR, Feltwell T, Feasey N, Parsons BN, Seth-Smith HM, Barquist L, Stedman A, Humphrey T, …, Dougan G, Thomson NR (2015)

PNAS 112 (3): 863-8

Signatures of adaptation in human invasive Salmonella Typhimurium ST313 populations from sub-Saharan Africa

Okoro CK, Barquist L, Connor TR, Harris SR, Clare S, Stevens MP, Arends MJ, Hale C, Kane L, Pickard DJ, …, Dougan G, Kingsley RA (2015)

PLOS Neglected Tropical Diseases 9 (3): e0003611

2014

Functional genomics reveals that Clostridium difficile Spo0A coordinates sporulation, virulence and metabolism

Pettit LJ, Browne HP, Yu L, Smits WK, Fagan RP, Barquist L, Martin MJ, Goulding D, Duncan SH, Flint HJ, …, Choudhary JS, Lawley TD (2014)

BMC Genomics 15: 160

Robust identification of noncoding RNA from transcriptomes requires phylogenetically-informed sampling

Lindgreen S, Umu SU, Lai AS, Eldai H, Liu W, McGimpsey S, Wheeler NE, Biggs PJ, Thomson NR, Barquist L, Poole AM, Gardner PP (2014)

PLOS Computational Biology 10 (10): e1003907

Parallel independent evolution of pathogenicity within the genus Yersinia

Reuter S, Connor TR, Barquist L, Walker D, Feltwell T, Harris SR, Fookes M, Hall ME, Petty NK, Fuchs TM, …, McNally A, Thomson NR (2014)

PNAS 111 (18): 6768-73

An introduction to RNA databases

Hoeppner MP, Barquist L, Gardner PP (2014)

In: RNA Sequence, Structure, and Function: Computational and Bioinformatic Methods (eds Gorodkin J, Ruzzo W), Methods Mol Biol 1097: 107-23

2013

Rfam 11.0: 10 years of RNA families

Burge SW, Daub J, Eberhardt R, Tate J, Barquist L, Nawrocki EP, Eddy SR, Gardner PP, Bateman A (2013)

Nucleic Acids Research 41 (Database issue): D226-32

RNA-seq reveals the RNA binding proteins, Hfq and RsmA, play various roles in virulence, antibiotic production and genomic flux in Serratia sp. ATCC 39006

Wilf NM, Reid AJ, Ramsay JP, Williamson NR, Croucher NJ, Gatto L, Hester SS, Goulding D, Barquist L, Lilley KS, …, Dougan G, Salmond GP (2013)

BMC Genomics 14: 822

A comparison of dense transposon insertion libraries in the Salmonella serovars Typhi and Typhimurium

Barquist L, Langridge GC, Turner DJ, Phan M, Turner AK, Bateman A, Parkhill J, Wain J, Gardner PP (2013)

Nucleic Acids Research 41 (8): 4549-64

Dominant role of nucleotide substitution in the diversification of serotype 3 pneumococci over decades and during a single infection

Croucher NJ, Mitchell AM, Gould KA, Inverarity D, Barquist L, Feltwell T, Fookes MC, Harris SR, Dordel J, Salter SJ, …, Mitchell TJ, Bentley SD (2013)

PLOS Genetics 9 (10): e1003868