Basak lab

Quantitative single cell biology of neural stem cells and cellular diversity

The cellular diversity of the human brain is immense, which is generated through evolutionarily conserved developmental mechanisms. The system is robust enough to create functional masterpiece; yet is susceptible to failure that may lead to cognitive dysfunction.

We study the molecular and cellular mechanisms behind brain development and how these are affected in autism spectrum disorder, as well as determine how histone methylation contributes to the cellular heterogeneity in the reward system of the adult brain. For this, we use state-of-the art single cell sequencing techniques, CRISPR-mediated gene inactivation, mouse genetics and computational tools to run multidisciplinary, collaborative projects

1. How do ASD-linked histone modifiers affect cell fate choices of neural stem cells?

Determining spatiotemporal pattern of autism-linked genes using single cell analysis.
We aim to delineate the molecular and cellular mechanisms behind epigenetic regulation of cell fate decisions of neural stem cells (NSCs) and how these mechanisms fail in mutations associated with autism spectrum disorder (ASD).
 
Our focus is on elucidating the role of ASD-linked histone modifiers Kdm5b and Ezh2 in late embryonic and early postnatal cortical development. To this end, we characterize the effect of Kdm5b and Ezh2 on proliferation, differentiation and migration of NCS as well as the effect on gene expression in NCS with the use of CRISPR-mediated gene inactivation through in utero electroporation.

2. How does histone methylation contribute to cellular heterogeneity in the adult reward system?

The ventral tegmental area (VTA) is part of the reward system and is characterized as having a heterogeneous cell population that are organized in neural populations that exhibit a more gradual transition, making it difficult to define VTA borders. Extensive research has been done on the VTA, however not on a single cell level. As part of the BRAINSCAPES consortium, we are using single cell RNAsequencing/ChIC-sequencing to generate a reference atlas of the heterogeneous cell population within the VTA.
 
Our project will provide a new resource whose quality, precision and depth exceeds current literature. This data can be reused by researchers analyzing traits linked to different mental disorders, such as depression, as well as those working on neurodegenerative disorders that affect the dopaminergic system, such as Parkinson’s Disease.
 
We also aim to determine how histone methylation contributes to the cellular heterogeneity in the adult brain and determine if long term histone modifications play a role in eating and stress disorders.

 

Our group is part of the Utrecht Bioinformatics Center that performs Life Science research using big data analysis on DNA, genes, proteins and cells.. For more information please visit https://ubc.uu.nl/user/obasak/

 

Dr. Onur Basak

Principle investigator
A coffee loving molecular biologist pretending to be a computational scientist, and leader of my pack!

 

Group members

Tiziana Hey, MSc – PhD student
Generating a single cell RNAseq/ChIC-seq reference atlas of the adult mouse VTA as part of the BRAINSCAPES consortium and determining how histone methylation contributes to the cellular heterogeneity and long term differences in perturbation within the reward system.

Single-cell omics, immunohistochemistry, Ventral Tegmental Area (VTA), cell/nuclei isolation from mouse brain.

Nine Lukassen, BSc – Master student (Neuroscience and Cognition)
Determining the role of ASD-linked Kdm5b in proliferation, differentiation and migration of neural stem cells and progenitors during cortical development using CRISPR-Cas9 mediated gene inactivation and performing an in vitro functional analysis of Kdm5b in NSCs.

Bram Schouten, BSc – Master student (Bioinformatics & Biocomplexity)
Currently working with published singe cell sequencing datasets to determine how autism-linked genes contribute to the generation of different cells types in the cortex, through reconstruction of lineage trajectories and construction of gene regulatory networks.

 

Recent papers

  1. Donega V, Burm SM, van Strien ME, van Bodegraven EJ, Paliukhovich I, Geut H, van de Berg WDJ, Li KW, Smit AB, Basak O, Hol EM. Transcriptome and proteome profiling of neural stem cells from the human subventricular zone in Parkinson’s disease. Acta Neuropathol Commun. 2019 Jun 3;7(1):84. doi: 10.1186/s40478-019-0736-0. Erratum in: Acta Neuropathol Commun. 2019 Aug 14;7(1):131. PMID: 31159890; PMCID: PMC6545684.
  2. Basak O, Krieger TG, Muraro MJ, Wiebrands K, Stange DE, Frias-Aldeguer J, Rivron NC, van de Wetering M, van Es JH, van Oudenaarden A, Simons BD, Clevers H. Troy+ brain stem cells cycle through quiescence and regulate their number by sensing niche occupancy. Proc Natl Acad Sci U S A. 2018 Jan 23;115(4):E610-E619. doi: 10.1073/pnas.1715911114. Epub 2018 Jan 8. PMID: 29311336; PMCID: PMC5789932.
  3. Basak O, Beumer J, Wiebrands K, Seno H, van Oudenaarden A, Clevers H. Induced Quiescence of Lgr5+ Stem Cells in Intestinal Organoids Enables Differentiation of Hormone-Producing Enteroendocrine Cells. Cell Stem Cell. 2017 Feb 2;20(2):177-190.e4. doi: 10.1016/j.stem.2016.11.001. Epub 2016 Dec 8. PMID: 27939219.
  4. Giachino C, Basak O, Lugert S, Knuckles P, Obernier K, Fiorelli R, Frank S, Raineteau O, Alvarez-Buylla A, Taylor V. Molecular diversity subdivides the adult forebrain neural stem cell population. Stem Cells. 2014 Jan;32(1):70-84. doi: 10.1002/stem.1520. PMID: 23964022; PMCID: PMC4259462.
  5. Basak O, Giachino C, Fiorini E, Macdonald HR, Taylor V. Neurogenic subventricular zone stem/progenitor cells are Notch1-dependent in their active but not quiescent state. J Neurosci. 2012 Apr 18;32(16):5654-66. doi: 10.1523/JNEUROSCI.0455-12.2012. PMID: 22514327; PMCID: PMC6703480.
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