Principal Investigator Boyan Bonev
3D Genome and Molecular Neurobiology

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.

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.

  • 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

Dr. Boyan Bonev

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_Bonev

Dr. Boyan Bonev

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

Postdoc

Dr. Florian Noack

E-Mail

PhD in Epigenetics and Cortical Development, CRTD Dresden, Technische Universität Dresden
Focus: gene regulatory networks of the developing cortex
Doctoral Thesis: “Mapping and manipulation of DNA modifications during cortical development”

PhD Student

Silvia Vangelisti

E-Mail

MSc in Molecular Biology, Università degli studi di Milano, Italy
Focus: 3D genome architecture rewiring in brain evolution
Master’s Thesis: “The over-expression of transcription factor BCL6 regulates the expression of miR-31 in näive CD4+ T cells”

Vera Manelli

E-Mail

MSc in Molecular Biology, Università degli studi di Milano, Italy
Focus: molecular mechanisms of chromatin looping
Master’s Thesis: “Physiological relevance of the stearoyltransferase ZDHHC6 in human cells and Drosophila Melanogaster”

 

Jei Diwakar

E-Mail 

MBioChem in Molecular and Cellular Biochemistry, University of Oxford, UK
Focus: transcription factor mediated rewiring of 3D genome architecture in development
Master’s Thesis: “Investigating the role of SETIA in gene induction”

Gerald Raffl

E-Mail 

Focus: imaging of dynamic enhancer-promoter interactions in neural development

Faye Chong

Focus: integration of single cell RNA and ATAC data to interpret cell heterogeneity during brain development

Lab Manager

Dr. Madalena Carido Pereira

E-Mail 

PhD in Retinal Neurobiology, CRTD Dresden, Technische Universität Dresden
Focus: effects of disease-related mutations on 3D genome architecture in human iPSCs
Doctoral Thesis: “Cell-based replacement of retinal pigment epithelium in rodent models of retinal degeneration”

Alumni

Kerstin Wagner

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

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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.
 

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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.
 

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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