Research Dr. Boyan Bonev

Our team is part of the Helmholtz Pioneer Campus, Munich, an initiative of the Helmholtz Zentrum München. We are temporarily hosted at the BMC of the LMU.

Short Bio

For his PhD work Boyan joined the Lab of Nancy Papalopulu at the University of Manchester, where he studied how microRNAs contribute to heterogeneity in neural stem cell. He pursued his postdoctoral studies in the laboratories of Paola Arlotta & John Rinn at Harvard University and Giacomo Cavalli at the Institute of Human Genetics – CNRS, respectively. His research resulted in major insights into how 3D genome organization contributes to cell fate identity during neural development.

Boyan is recipient of the prestigious Wellcome Trust PhD Fellowship (2007) and the Sir Henry Wellcome Postdoctoral Fellowship (2013). He has been awarded the Beddington Medal for best PhD thesis in Developmental Biology by the British Society for Developmental Biology (2012) and the Great Advances in Biology Award by the French Academy of Sciences (2018)

Boyan will join the Helmholtz Pioneer Campus on August 1, 2018.

Research

Figure adapted from Woodworth et al., 2012

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.

In order to accomplish this, we pursue the following major directions of research:

(I) 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.

Collectively, these experiments will address whether two (or more) populations of progenitors co-exist (so cells are primed to differentiate into different types of neurons early on) and allow us to identify novel factors involved in the restriction of fate potential. They will also shed light if changes in 3D chromatin conformation precede transcription or vice versa and allow us to build a comprehensive picture of the interplay between genome folding and transcription in generating identities of individual cells.

(II) 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.

Collectively, these experiments will shed light on the functional consequences for neuronal subtype specification in vivo and address the importance of 3D chromatin architecture remodeling by transcription factors for the progressive restriction of lineage potential in progenitor cells.

(III) 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.

These experiments will establish a new paradigm for rewiring of regulatory interactions during evolution based on local chromatin topology and identify new mechanisms, which may have contributed to the expansion of the cortex in the primate lineage. The use of the organoid system also allows us to test the effect of disease related mutations in associated with chromatin remodeling proteins on 3D chromatin architecture and cell fate using genetically modified human iPSCs.

Our research is highly interdisciplinary and combines developmental neurobiology, single cell –omics, mouse genetics, CRISPR-based techniques and computational biology. Collectively, our long-term objective is to decipher the genetic and epigenetic blueprints of cortical development and establish new paradigms into the interplay between transcription factors, chromatin topology and gene expression during development in vivo.

Selected Publications

Bonev B, Mendelson Cohen N, Szabo Q, Fritsch L, Papadopoulos GL, Lubling Y, Xu X, Lv X, Hugnot JP, Tanay A, Cavalli G.
Multiscale 3D Genome Rewiring during Mouse Neural Development.
Cell. 2017 Oct 19;171(3):557-572.e24.

Bonev B, Cavalli G.
Organization and function of the 3D genome.
Nat Rev Genet. 2016 Dec;17(12):772.

Bonev B, Stanley P, Papalopulu N.
MicroRNA-9 Modulates Hes1 ultradian oscillations by forming a double-negative feedback loop.
Cell Rep. 2012 Jul 26;2(1):10-8.

Bonev B, Pisco A, Papalopulu N.
MicroRNA-9 reveals regional diversity of neural progenitors along the anterior-posterior axis.
Dev Cell. 2011 Jan 18;20(1):19-32.

Join the Team

Mentoring and training the next generation of brilliant scientists is one of the top priorities in our lab. We want to ensure that every member of the lab is able to fulfil their maximum potential and enjoy their time with minimal internal pressure. All lab members will receive sufficient guidance, training and support and will have the opportunity to investigate independent questions.

As a young lab, we are much more committed to ensure that each and every person in the lab is successful and feels valued. We have secure funding for at least 5 years and you will have the opportunity to experience and influence a fresh lab atmosphere.

Contact

Dr. Boyan Bonev
Team Leader
E-Mail

Lab Website

Google Scholar

 

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