Gene expression genomics

Sarah's research uses genomic approaches to study global regulation of gene expression in the mouse immune system.

Sarah's research uses genomic approaches to study global regulation of gene expression in the mouse immune system. Using both laboratory-based and computational techniques, the group studies phenotypic switches in cell state, specifically during the dynamic responses that occur in the immune system.

While the genomic DNA template is static, dynamic changes in gene expression lead to specification of cells and tissues. The immune system is a particular dramatic example of this, where cells differentiate very rapidly in response to a challenge. We exploit the power of next-generation sequencing to discover global principles of gene expression regulation, and focus on immune responses.

[Sarah Teichmann]

Background

Any switch in cell state, such as those occurring during differentiation, development or reprogramming, is orchestrated by a complex transcriptional regulatory network and accompanied by global changes in transcriptomes. We aim to to decode the hierarchy and regulatory switches involved in changes in cell state, and identify patterns and principles that govern transitions in cellular transcriptomes. Despite decades of research, cells of the immune system, their development and differentiation, are still incompletely understood at the cellular and molecular levels, and new genomic and quantitative approaches have the potential to provide profound new insights.

Research

Our long-term goal is to understand how changes in cell state are regulated at the transcriptomic and epigenetic levels. We pursue this goal using an integrated computational and experimental approach. The Teichmann group, along with our collaborators, use cellular differentiation events that occur in the immune system as models of general principles of switches in cell state. Lymphocytes such as T cells are experimentally amenable in vitro and in vivo, and central to human health in processes such as infection, autoimmunity, pregnancy and cancer.

Decoding genetic switches in T helper cell differentiation

We investigate the molecular basis and kinetics of changes in gene expression levels during Th differentiation and interconversion. During these processes, networks of transcriptional regulatory interactions switch expression levels of hundreds of genes. In order to identify the interactions, we study the transcriptional and epigenetic changes accompanying proliferation-dependent differentiation processes: a key innovation is very high temporal resolution (individual cell divisions), and a genome-wide view using next generation sequencing techniques (ChIP-seq and RNA-seq). This allows us to unravel the differentiation process by integrating the cellular, molecular and genomic data through multi-scale mathematical modeling.

Single cell transcriptomics

Advances in microfluidics and next generation sequencing harbour huge potential for profiling transcriptomes accurately in 100s of single cells at a time. Single cell RNA-sequencing will redefine how we describe and identify a cell state and will give us a new window on the extent of heterogeneity in cell populations.

Collaborations

We collaborate on gene expression genomics with many groups in the Cambridge area and around the world, including:

  • Madan Babu, Systems biology, MRC Laboratory of Molecular Biology, Cambridge, UK
  • Alex Betz, The initiation of immune responses, MRC Laboratory of Molecular Biology, Cambridge, UK
  • Bertie Goettgnes, Haematopoietic stem cell laboratory, Cambridge Institute for Medical Research, Cambridge, UK
  • John Marioni, Marioni Group, EMBL-EBI
  • Andrew McKenzie, Transgenic models of immune and haematopoietic disorders, MRC Laboratory of Molecular Biology, Cambridge, UK
  • Mario Nicodemi, Statistical physics, computational and system biology, University of Naples, Italy
  • Willem Ouwehand, NHS Blood and Transplant research group, Haematology, Cambridge, UK
  • Ana Pombo, Genome function, Berlin, Germany
  • Azim Surani, Mammalian germ cells, pluripotency and epigenesis, Gurdon Institute, Cambridge, UK
  • Thierry Voet, Single-cell genomics, Wellcome Trust Sanger Institute and Laboratory of Reproductive Genomics, Department of Human Genetics, KU Leuven, Belgium

Selected Publications

  • DNA sequence preferences of transcriptional activators correlate more strongly than repressors with nucleosomes.

    Charoensawan V, Janga SC, Bulyk ML, Babu MM and Teichmann SA

    Molecular cell 2012;47;2;183-92

    PUBMED: 22841002; PMC: 3566590; DOI: 10.1016/j.molcel.2012.06.028

  • EpiChIP: gene-by-gene quantification of epigenetic modification levels.

    Hebenstreit D, Gu M, Haider S, Turner DJ, Liò P and Teichmann SA

    Nucleic acids research 2011;39;5;e27

    PUBMED: 21131282; PMC: 3061070; DOI: 10.1093/nar/gkq1226

  • RNA sequencing reveals two major classes of gene expression levels in metazoan cells.

    Hebenstreit D, Fang M, Gu M, Charoensawan V, van Oudenaarden A and Teichmann SA

    Molecular systems biology 2011;7;497

    PUBMED: 21654674; PMC: 3159973; DOI: 10.1038/msb.2011.28

  • The impact of gene expression regulation on evolution of extracellular signaling pathways.

    Charoensawan V, Adryan B, Martin S, Söllner C, Thisse B, Thisse C, Wright GJ and Teichmann SA

    Molecular & cellular proteomics : MCP 2010;9;12;2666-77

    PUBMED: 20935258; PMC: 3101855; DOI: 10.1074/mcp.M110.003020

  • DBD--taxonomically broad transcription factor predictions: new content and functionality.

    Wilson D, Charoensawan V, Kummerfeld SK and Teichmann SA

    Nucleic acids research 2008;36;Database issue;D88-92

    PUBMED: 18073188; PMC: 2238844; DOI: 10.1093/nar/gkm964

  • Gene regulatory network growth by duplication.

    Teichmann SA and Babu MM

    Nature genetics 2004;36;5;492-6

    PUBMED: 15107850; DOI: 10.1038/ng1340

Team

No team members listed

* quick link - http://q.sanger.ac.uk/xpt3vthu