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.
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.
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.
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.
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.
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
Honors and Awards
Great Advances in Biology Award, French Academy of Sciences
Best Poster Award, EMBO Gene regulation in neural fate decisions
2013 - 2017
Sir Henry Wellcome Postdoctoral Fellowship
Beddington Medal for best PhD thesis in Developmental Biology, British Society for Developmental Biology
2007 - 2011
Wellcome Trust PhD Fellowship
Best Poster Award, Faculty Research Symposium Manchester
Best Presentation Award, Faculty Showcase Symposium, Manchester
2001 & 2002
Gold Medal, Bulgarian National Olympiad in Biology
EMBO Nuclear Structure and Dynamics (France) - Invited Speaker
REDbrain Conference (Switzerland) - Invited speaker
EMBO Gene regulatory mechanisms in neural fate decisions (Spain) - Poster presentation
Cortical Development Conference (Greece) - Invited speaker
EMBO Chromatin & Epigenetics (Germany) - Poster presentation
Architecture and Plasticity of the Cell Nucleus (France) - Poster presentation
EpiGeneSys Conference (France) - Invited speaker
Genome Regulation in 3D (Israel) - Poster presentation
EMBO Nuclear Structure and Dynamics (France) - Poster presentation
Neuro-RNA Symposium – Boston (US) - Invited speaker
BSCB/BSDB/JSDB Joint Meeting (UK) - Invited speaker
Company of Biologists Cell Cycle workshop (UK) - Session chair
Non-coding RNA, Epigenetic Memory (UK) - Invited speaker
Keystone Mechanism and Biology of Silencing (US) - Poster presentation
EMBO The Non-coding Genome (Germany) - Invited speaker
13th International Xenopus Meeting (Canada) - Poster presentation
miRNAs, siRNAs and non-coding RNAs (UK) - Invited speaker
London LRI Symposium on Developmental Biology (UK) - Poster presentation
UK Xenopus Meeting, Warwick (UK) - Invited speaker
Brain Development Symposium, London (UK) - Poster presentation
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”
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”
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”
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”
Focus: integration of single cell RNA and ATAC data to interpret cell heterogeneity during brain development
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”
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.
Bonev B, Stanley P, Papalopulu N.
Cell Rep. 2012 Jul 26;2(1):10-8. doi: 10.1016/j.celrep.2012.05.017.
Bonev B, Pisco A, Papalopulu N.
Dev Cell. 2011 Jan 18;20(1):19-32. doi: 10.1016/j.devcel.2010.11.018.
Helmholtz Pioneer Campus
Helmholtz Zentrum München
Deutsches Forschungszentrum für Gesundheit und Umwelt (GmbH)
Biomedical Center (BMC)
Room NC 03.010
Großhaderner Strasse 9