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Principal Investigator Boyan Bonev
3D Genome and Molecular Neurobiology

Research

The mammalian cortex is the most complex region of the brain responsible for higher cognitive functions. Abnormal cortical development often translates into prominent neuropsychiatric diseases, which affect different neuronal subtypes with unique molecular and morphological features. There is increasing evidence that epigenetic regulation of key neural genes is essential for subtype specification and that spatial gene positioning and 3D chromatin folding is crucial for cell fate choices in development, evolution and disease. Therefore a fundamental question in the field is: how is epigenetic identity related to cell fate and what are the functional implication of chromatin remodeling to the temporal and spatial heterogeneity in the cortex? The Bonev Lab focuses on decoding the epigenetic mechanisms of gene regulation in the cortex and how they control temporal and spatial cellular identity in development and evolution.

     

     

    Our Vision

    • To understand the genomic blueprints guiding billions of neurons to assemble in the most complicated object in the universe – our brain
    • To challenge the current status quo by employing interdisciplinary ideas, methods and model organisms
    • To think differently and to make a lasting impact in the fields of epigenetics, developmental biology and neuroscience
       

    To achieve these goals we will

    • Develop a lab culture where the focus is on people and they are valued, respected and trusted
    • Abandon assumptions and dogmas and embrace “First Principles” approaches
    • Go beyond state-of-the-art and always challenge ourselves to do better

     

     

    Projects

    Define epigenetic and transcriptional heterogeneity in the cortex at the single cell level

    To understand how the cortex is built, we need to be able to study how cellular identity evolves in time, ideally at the single cell level. Importantly, chromatin accessibility and 3D genome organization carry unique information that is not provided by single-cell RNAseq and epigenome changes may precede gene expression. Recent breakthroughs in methodology have allowed chromatin structure to be interrogated even at the single-cell level. Therefore, we are in an ideal and timely position to address the spatio-temporal dynamics of gene regulation and 3D nuclear organization in the cortex.

    We are developing a highly innovative genomics approach to simultaneously interrogate gene expression and chromatin topology at single-cell level. In addition, we use a combination of single-cell lineage tracing using CRISPR, scATAC-seq and spatial transcriptomics to understand how lineage potential is encoded spatially and temporally in neural stem cells.

     

    Determine how transcription factors and ncRNAs remodel the 3D genome

    We have previously discovered that regulating 3D chromatin architecture and enhancer-promoter interactions plays an important role in the control of gene expression and cell fate in the cortex. Furthermore, several key transcription factors and potentially some long non-coding RNAs are associated at the molecular level with dynamic chromatin loops and may function mechanistically by remodeling genome topology.

    However, a key unresolved question in the field is if TF binding and/or lncRNAs can physically affect nuclear 3D architecture or simply exploit it in order to spread and bind on chromatin. To disentangle cause and consequence, we are using transgenic mouse lines and CRISPR-Cas9 genome engineering to determine if TF binding is sufficient to induce an ectopic chromatin looping and rewire 3D genome architecture in vivo.

     

    Dissect the changes in 3D genome topology during brain evolution

    Cortical evolution in mammals is considered to be a key advance that enabled higher cognitive function such as language. Structural variations including indels, inversions and duplications account for 3-4 times more sequence divergence between the chimpanzee and the human genomes than single-base-pair mutations. Yet, almost all of the comparative evolution studies trying to understand what makes the human brain unique focus on SNPs in coding genes or putative enhancer regions based on proximity to important neural genes. Recent advances in chromatin biology and our own work suggest that changes in 3D architecture can strongly affect gene expression of regions in close physical proximity and not necessarily on the linear 1D genome.

    Therefore, we are systematically examining how 3D chromatin organization has changed during primate evolution focusing on the cortex. We use cerebral organoids from mouse, macaque, chimp and human iPSC and compare them with in vivo models of corticogenesis such as the ferret and the human fetal cortex. We will also examine the functional importance of the most promising structural variations using organoids and in mice using the CRISPR-Cas9 system.

     

    Boyan Bonev, PhD

    Principal Investigator, 3D Genome and Molecular Neurobiology

    Our long-term objective is to decipher the genetic and epigenetic blueprints of cortical development and evolution. To accomplish this, we study the interplay between transcription factors, 3D nuclear organization and gene expression in vivo and using cerebral organoids. Our research is highly interdisciplinary and combines developmental neurobiology, single cell –omics, mouse genetics, CRISPR-based techniques and computational biology.

      Factsheet

      Boyan Bonev, PhD

      Positions and Career

      2018 - present
      Principal Investigator Helmholtz Pioneer Campus, Helmholtz Zentrum München

      2014 – 2018
      Postdoctoral Fellow Institute of Human Genetics – CNRS (France)   
      Mentor: Giacomo Cavalli

      2012 – 2013
      Postdoctoral Fellow Harvard University (United States)
      Mentor: Paola Arlotta & John Rinn

       

      2007 – 2012
      Wellcome Trust PhD University of Manchester (United Kingdom) 
      Nancy Papalopulu Lab “Role of microRNA-9 in vertebrate neural development”

      2003 – 2007
      BSc in Biotechnology Mannheim University of Applied Sciences (Germany) 
      Blanche Schwappach Lab 

       

      2018
      Great Advances in Biology Award, French Academy of Sciences

      2017
      Best Poster Award, EMBO Gene regulation in neural fate decisions

      2013 - 2017
      Sir Henry Wellcome Postdoctoral Fellowship

      2012
      Beddington Medal for best PhD thesis in Developmental Biology, British Society for Developmental Biology

      2007 - 2011
      Wellcome Trust PhD Fellowship

      2011
      Best Poster Award, Faculty Research Symposium Manchester

      2010
      Best Presentation Award, Faculty Showcase Symposium, Manchester

      2001 & 2002
      Gold Medal, Bulgarian National Olympiad in Biology

       

      2017
      EMBO Nuclear Structure and Dynamics (France) - Invited Speaker

      2017
      REDbrain Conference (Switzerland) - Invited speaker

      2017
      EMBO Gene regulatory mechanisms in neural fate decisions (Spain) - Poster presentation

      2017
      Cortical Development Conference (Greece) - Invited speaker

      2017
      EMBO Chromatin & Epigenetics (Germany) - Poster presentation

      2016
      Architecture and Plasticity of the Cell Nucleus (France) - Poster presentation

      2016
      EpiGeneSys Conference (France) - Invited speaker

      2015
      Genome Regulation in 3D (Israel) - Poster presentation

      2015
      EMBO Nuclear Structure and Dynamics (France) - Poster presentation

      2013
      Neuro-RNA Symposium – Boston (US) - Invited speaker

      2012
      BSCB/BSDB/JSDB Joint Meeting (UK) - Invited speaker

      2011
      Company of Biologists Cell Cycle workshop (UK) - Session chair

      2011
      Non-coding RNA, Epigenetic Memory (UK) - Invited speaker

      2011
      Keystone Mechanism and Biology of Silencing (US) - Poster presentation

      2010
      EMBO The Non-coding Genome (Germany) - Invited speaker

      2010
      13th International Xenopus Meeting (Canada) - Poster presentation

      2010
      miRNAs, siRNAs and non-coding RNAs (UK) - Invited speaker

      2009
      London LRI Symposium on Developmental Biology (UK) - Poster presentation

      2009
      UK Xenopus Meeting, Warwick (UK) - Invited speaker

      2008
      Brain Development Symposium, London (UK) - Poster presentation

       

      Lab Manager

      Kerstin Wagner

      E-Mail 

      Postdoc

      Florian Noack

      E-Mail

      PhD Student

      Silvia Vangelisti

      E-Mail

      Selected Publications

      Multiscale 3D Genome Rewiring during Mouse Neural Development.

      Bonev B*, Mendelson Cohen N, Szabo Q, Fritsch L, Papadopoulos GL, Lubling Y, Xu X, Lv X, Hugnot JP, Tanay A, Cavalli G*.
      Cell. 2017 Oct 19;171(3):557-572.e24. doi: 10.1016/j.cell.2017.09.043.
      *Co-corresponding authors

      More Details

      Organization and function of the 3D genome.

      Bonev B, Cavalli G.
      Nat Rev Genet. 2016 Dec;17(12):772. doi: 10.1038/nrg.2016.147. 
       

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      MicroRNA-9 Modulates Hes1 ultradian oscillations by forming a double-negative feedback loop.

      Bonev B, Stanley P, Papalopulu N.
      Cell Rep. 2012 Jul 26;2(1):10-8. doi: 10.1016/j.celrep.2012.05.017.
       

      More Details

      MicroRNA-9 reveals regional diversity of neural progenitors along the anterior-posterior axis.

      Bonev B, Pisco A, Papalopulu N.
      Dev Cell. 2011 Jan 18;20(1):19-32. doi: 10.1016/j.devcel.2010.11.018.
       

      More Details

      Contact us

      HPC Contact Bonev

      Contact

       

      Helmholtz Pioneer Campus
      Helmholtz Zentrum München
      Deutsches Forschungszentrum für Gesundheit und Umwelt (GmbH)

      Current address:

      Biomedical Center (BMC) 
      Ludwig-Maximilians-Universität München 
      Room NC 03.010 
      Großhaderner Strasse 9 
      82152 Planegg-Martinsried 
      Germany