Lebenslauf

Publikationen

2018

Chromatin remodeling BAF155 subunit regulates the genesis of basal progenitors in developing cortex .
Narayanan R, Pham L, Kerimoglu C, Watanabe T, Hernandez RC, Sokpor G, Ulmke PA, Kiszka KA, Tonchev AB, Rosenbusch J, Seong RH, Teichmann U, Frahm J, Fischer F, Bonn S, Stoykova A, Staiger JF, Tuoc T.
iScience (Cell Press), DOI: https://doi.org/10.1016/j.isci.2018.05.014, 2018.
abstract link

The abundance of basal progenitors (BPs) - basal radial glia progenitors (bRGs) and basal intermediate progenitors (bIPs), in primate brain has been correlated to the high degree of cortical folding. Here we examined the role of BAF155, a subunit of the chromatin remodeling BAF complex, in generation of cortical progenitor heterogeneity. The conditional deletion of BAF155 led to diminished bIP pool and increased number of bRGs, due to delamination of apical RGs. We found that BAF155 is required for normal activity of neurogenic transcription factor PAX6, thus controlling expression of genes that are involved in bIP specification, cell-cell interaction and establishment of adherens junction. In PAX6-dependent manner, BAF155 regulates the expression of the CDC42 effector protein CEP4, thereby controlling progenitor delamination. Furthermore, BAF155-dependent chromatin remodeling seems to exert a specific role in the genesis of BPs through regulation of human RG-specific genes (such as Foxn4) that possibly acquired evolutionary significance.

Epigenetic regulation by BAF (mSWI/SNF) complexes limits neural stem cell proliferation by suppressing Wnt signaling in late embryonic development.
Nguyen H*, Kerimoglu C*, Pirouz M, Pham L, Kiszka KA, Sokpor G, Sakib MS, Rosenbusch J, Teichmann U, Seong RH, Stoykova A, Fischer A, Staiger JF, Tuoc T .
Stem Cell Reports, doi: 10.1016/j.stemcr.2018.04.014, 2018.
abstract link

During early cortical development, neural stem cells (NSCs) divide symmetrically to expand the progenitor pool, whereas in later stages, NSCs divide asymmetrically to self-renew and produce other cell types. The timely switch from such proliferative to differentiative division critically determines progenitor and neuron numbers. However, the mechanisms that limit proliferative division in late cortical development are not fully understood. Here, we show that the BAF (mSWI/SNF) complexes restrict proliferative competence and promote neuronal differentiation in late corticogenesis. Inactivation of BAF complexes leads to H3K27me3-linked silencing of neuronal differentiation-related genes, with concurrent H3K4me2-mediated activation of proliferation-associated genes via de-repression of Wnt signaling. Notably, the deletion of BAF complexes increased proliferation of neuroepithelial cell-like NSCs, impaired neuronal differentiation and exerted a Wnt-dependent effect on neocortical and hippocampal development. Thus, these results demonstrate that BAF complexes act as both activators and repressors to control global epigenetic and gene expression programs in late corticogenesis.

2015

Loss of BAF (mSWI/SNF) complexes causes global transcriptional and chromatin state changes in forebrain development.
Ramanathan Narayanan, Mehdi Pirouz, Cemil Kerimoglu, Linh Pham, Robin J. Wagener, Kamila A. Kiszka, Joachim Rosenbusch, Michael Kessel, Andre Fischer, Anastassia Stoykova, Jochen F. Staiger, and Tran Tuoc.
Cell Reports, 2015. 13, 1–13
abstract link

BAF (Brg/Brm-associated factors) complexes play important roles in development and are linked to chromatin plasticity at selected genomic loci. Nevertheless, a full understanding of their role in development and chromatin remodeling has been hindered by the absence of mutants completely lacking BAF complexes. Here, we report that the loss of BAF155/BAF170 in double-conditional knock-out (dcKO) mice eliminates all known BAF subunits, resulting in an overall reduction in active chromatin marks (H3K9Ac), a global increase in repressive marks (H3K27me2/3), and down-regulation of gene expression. We demonstrate that BAF complexes interact with H3K27 demethylases (JMJD3, UTX) and potentiate their activity. Importantly BAF complexes are indispensable for forebrain development, including proliferation, differentiation and cell survival of neural progenitor cells. Our findings reveal a molecular mechanism mediated by BAF complexes that controls global transcriptional program and chromatin state in development.