Genome Biology Unit

Heidelberg, Germany

Genome Biology Unit

Heidelberg, Germany
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Velten L.,Genome Biology Unit
Nature Cell Biology | Year: 2017

Blood formation is believed to occur through stepwise progression of haematopoietic stem cells (HSCs) following a tree-like hierarchy of oligo-, bi- and unipotent progenitors. However, this model is based on the analysis of predefined flow-sorted cell populations. Here we integrated flow cytometric, transcriptomic and functional data at single-cell resolution to quantitatively map early differentiation of human HSCs towards lineage commitment. During homeostasis, individual HSCs gradually acquire lineage biases along multiple directions without passing through discrete hierarchically organized progenitor populations. Instead, unilineage-restricted cells emerge directly from a ‘continuum of low-primed undifferentiated haematopoietic stem and progenitor cells’ (CLOUD-HSPCs). Distinct gene expression modules operate in a combinatorial manner to control stemness, early lineage priming and the subsequent progression into all major branches of haematopoiesis. These data reveal a continuous landscape of human steady-state haematopoiesis downstream of HSCs and provide a basis for the understanding of haematopoietic malignancies. © 2017 Nature Publishing Group

Typas A.,University of California at San Francisco | Typas A.,Genome Biology Unit | Banzhaf M.,Harvard University | Gross C.A.,University of California at San Francisco | Vollmer W.,Northumbria University
Nature Reviews Microbiology | Year: 2012

How bacteria grow and divide while retaining a defined shape is a fundamental question in microbiology, but technological advances are now driving a new understanding of how the shape-maintaining bacterial peptidoglycan sacculus grows. In this Review, we highlight the relationship between peptidoglycan synthesis complexes and cytoskeletal elements, as well as recent evidence that peptidoglycan growth is regulated from outside the sacculus in Gram-negative bacteria. We also discuss how growth of the sacculus is sensitive to mechanical force and nutritional status, and describe the roles of peptidoglycan hydrolases in generating cell shape and of D-amino acids in sacculus remodelling. © 2012 Macmillan Publishers Limited. All rights reserved.

Korbel J.O.,Genome Biology Unit | Campbell P.J.,Wellcome Trust Sanger Institute | Campbell P.J.,Addenbrookes Hospital | Campbell P.J.,University of Cambridge
Cell | Year: 2013

Chromothripsis scars the genome when localized chromosome shattering and repair occurs in a one-off catastrophe. Outcomes of this process are detectable as massive DNA rearrangements affecting one or a few chromosomes. Although recent findings suggest a crucial role of chromothripsis in cancer development, the reproducible inference of this process remains challenging, requiring that cataclysmic one-off rearrangements be distinguished from localized lesions that occur progressively. We describe conceptual criteria for the inference of chromothripsis, based on ruling out the alternative hypothesis that stepwise rearrangements occurred. Robust means of inference may facilitate in-depth studies on the impact of, and the mechanisms underlying, chromothripsis. © 2013 Elsevier Inc.

Spitz F.,European Molecular Biology Laboratory | Furlong E.E.M.,Genome Biology Unit
Nature Reviews Genetics | Year: 2012

Developmental progression is driven by specific spatiotemporal domains of gene expression, which give rise to stereotypically patterned embryos even in the presence of environmental and genetic variation. Views of how transcription factors regulate gene expression are changing owing to recent genome-wide studies of transcription factor binding and RNA expression. Such studies reveal patterns that, at first glance, seem to contrast with the robustness of the developmental processes they encode. Here, we review our current knowledge of transcription factor function from genomic and genetic studies and discuss how different strategies, including extensive cooperative regulation (both direct and indirect), progressive priming of regulatory elements, and the integration of activities from multiple enhancers, confer specificity and robustness to transcriptional regulation during development. © 2012 Macmillan Publishers Limited. All rights reserved.

Raja S.J.,Genome Biology Unit
Molecular cell | Year: 2010

Here, we report the biochemical characterization of the nonspecific lethal (NSL) complex (NSL1, NSL2, NSL3, MCRS2, MBD-R2, and WDS) that associates with the histone acetyltransferase MOF in both Drosophila and mammals. Chromatin immunoprecipitation-Seq analysis revealed association of NSL1 and MCRS2 with the promoter regions of more than 4000 target genes, 70% of these being actively transcribed. This binding is functional, as depletion of MCRS2, MBD-R2, and NSL3 severely affects gene expression genome wide. The NSL complex members bind to their target promoters independently of MOF. However, depletion of MCRS2 affects MOF recruitment to promoters. NSL complex stability is interdependent and relies mainly on the presence of NSL1 and MCRS2. Tethering of NSL3 to a heterologous promoter leads to robust transcription activation and is sensitive to the levels of NSL1, MCRS2, and MOF. Taken together, we conclude that the NSL complex acts as a major transcriptional regulator in Drosophila. Copyright (c) 2010 Elsevier Inc. All rights reserved.

Typas A.,Genome Biology Unit | Sourjik V.,Max Planck Institute for Terrestrial Microbiology
Nature Reviews Microbiology | Year: 2015

Distinct cellular functions are executed by separate groups of proteins, organized into complexes or functional modules, which are ultimately interconnected in cell-wide protein networks. Understanding the structures and operational modes of these networks is one of the next great challenges in biology, and microorganisms are at the forefront of research in this field. In this Review, we present our current understanding of bacterial protein networks, their general properties and the tools that are used for systematically mapping and characterizing them. We then discuss two well-studied examples, the chemotaxis network and the cell cycle network in Escherichia coli, to illustrate how network architecture promotes function. © 2015 Macmillan Publishers Limited. All rights reserved.

Pelechano V.,Genome Biology Unit | Wei W.,Stanford University | Steinmetz L.M.,Genome Biology Unit | Steinmetz L.M.,Stanford University
Cell | Year: 2015

It is generally assumed that mRNAs undergoing translation are protected from decay. Here, we show that mRNAs are, in fact, co-translationally degraded. This is a widespread and conserved process affecting most genes, where 5′-3′ transcript degradation follows the last translating ribosome, producing an in vivo ribosomal footprint. By sequencing the ends of 5′ phosphorylated mRNA degradation intermediates, we obtain a genomewide drug-free measurement of ribosome dynamics. We identify general translation termination pauses in both normal and stress conditions. In addition, we describe novel codon-specific ribosomal pausing sites in response to oxidative stress that are dependent on the RNase Rny1. Our approach is simple and straightforward and does not require the use of translational inhibitors or in vitro RNA footprinting that can alter ribosome protection patterns. © 2015 Elsevier Inc.

Pelechano V.,Genome Biology Unit | Steinmetz L.M.,Genome Biology Unit | Steinmetz L.M.,Stanford University
Nature Reviews Genetics | Year: 2013

Antisense transcription, which was initially considered by many as transcriptional noise, is increasingly being recognized as an important regulator of gene expression. It is widespread among all kingdoms of life and has been shown to influence-either through the act of transcription or through the non-coding RNA that is produced-almost all stages of gene expression, from transcription and translation to RNA degradation. Antisense transcription can function as a fast evolving regulatory switch and a modular scaffold for protein complexes, and it can 'rewire' regulatory networks. The genomic arrangement of antisense RNAs opposite sense genes indicates that they might be part of self-regulatory circuits that allow genes to regulate their own expression.

Weischenfeldt J.,Genome Biology Unit | Symmons O.,European Molecular Biology Laboratory | Spitz F.,European Molecular Biology Laboratory | Korbel J.O.,Genome Biology Unit
Nature Reviews Genetics | Year: 2013

Genomic structural variants have long been implicated in phenotypic diversity and human disease, but dissecting the mechanisms by which they exert their functional impact has proven elusive. Recently however, developments in high-throughput DNA sequencing and chromosomal engineering technology have facilitated the analysis of structural variants in human populations and model systems in unprecedented detail. In this Review, we describe how structural variants can affect molecular and cellular processes, leading to complex organismal phenotypes, including human disease. We further present advances in delineating disease-causing elements that are affected by structural variants, and we discuss future directions for research on the functional consequences of structural variants. © 2013 Macmillan Publishers Limited. All rights reserved.

Anders S.,Genome Biology Unit | Pyl P.T.,Genome Biology Unit | Huber W.,Genome Biology Unit
Bioinformatics | Year: 2015

Motivation: A large choice of tools exists for many standard tasks in the analysis of high-throughput sequencing (HTS) data. However, once a project deviates from standard workflows, custom scripts are needed. Results: We present HTSeq, a Python library to facilitate the rapid development of such scripts. HTSeq offers parsers for many common data formats in HTS projects, as well as classes to represent data, such as genomic coordinates, sequences, sequencing reads, alignments, gene model information and variant calls, and provides data structures that allow for querying via genomic coordinates. We also present htseq-count, a tool developed with HTSeq that preprocesses RNA-Seq data for differential expression analysis by counting the overlap of reads with genes. © The Author 2014. Published by Oxford University Press. All rights reserved.

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