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Publikationen

2022

BAF (mSWI/SNF) complex regulates mediolateral cortical patterning in the developing forebrain.
Huong Nguyen, Godwin Sokpor, Arpan Parichha, Linh Pham, Nidhi Saikhedkar, Yuanbin Xie, Pauline Antonie Ulmke, Joachim Rosenbusch, Mehdi Pirouz, Rüdiger Behr, Anastassia Stoykova, Beate Brand-Saberi, Huu Phuc Nguyen, Jochen F. Staiger, Shubha Tole and Tran Tuoc.
Front. Cell Dev. Biol. 10:1011109. doi: 10.3389/fcell.2022.1011109, 2022.
abstract

Early forebrain patterning entails the correct regional designation of theneuroepithelium, and appropriate specification, generation, and distributionof neural cells during brain development. Specific signaling and transcriptionfactors are known to tightly regulate patterning of the dorsal telencephalon toafford proper structural/functional cortical arealization and morphogenesis.Nevertheless, whether and how changes of the chromatin structure link to thetranscriptional program(s) that control cortical patterning remains elusive. Here,we report that the BAF chromatin remodeling complex regulates thespatiotemporal patterning of the mouse dorsal telencephalon. To determinewhether and how the BAF complex regulates cortical patterning, weconditionally deleted the BAF complex scaffolding subunits BAF155 andBAF170 in the mouse dorsal telencephalic neuroepithelium. Morphologicaland cellular changes in the BAF mutant forebrain were examined usingimmunohistochemistry and in situ hybridization. RNA sequencing, Coimmunoprecipitation,and mass spectrometry were used to investigate themolecular basis of BAF complex involvement in forebrain patterning. We foundthat conditional ablation of BAF complex in the dorsal telencephalonneuroepithelium caused expansion of the cortical hem and medial cortexbeyond their developmental boundaries. Consequently, the hippocampalprimordium is not specified, the mediolateral cortical patterning iscompromised, and the cortical identity is disturbed in the absence of BAFcomplex. The BAF complex was found to interact with the cortical hemsuppressor LHX2. The BAF complex suppresses cortical hem fate to permitproper forebrain patterning. We provide evidence that BAF complex modulatesmediolateral cortical patterning possibly by interacting with the transcriptionfactor LHX2 to drive the LHX2-dependent transcriptional program essential fordorsal telencephalon patterning. Our data suggest a putative mechanisticsynergy between BAF chromatin remodeling complex and LHX2 inregulating forebrain patterning and ontogeny.

2021

H3 acetylation selectively promotes basal progenitor proliferation and neocortex expansion.
Cemil Kerimoglu, Linh Pham, Anton B. Tonchev, M. Sadman Sakib, Yuanbin Xie, Godwin Sokpor, Pauline Antonie Ulmke, Lalit Kaurani, Eman Abbas, Huong Nguyen, Joachim Rosenbusch, Alexandra Michurina, Vincenzo Capece, Meglena Angelova, Nenad Maricic, Beate Brand-Saberi, Miriam Esgleas, Mareike Albert, Radoslav Minkov, Emil Kovachev, Ulrike Teichmann, Rho H. Seong, Wieland B. Huttner, Huu Phuc Nguyen, Anastassia Stoykova, Jochen F. Staiger, Andre Fischer, Tran Tuoc.
Science Advances 2021; 7 : eabc6792, 2021.
abstract link

Increase in the size of human neocortex―acquired in evolution―accounts for the unique cognitive capacity ofhumans. This expansion reflects the evolutionarily enhanced proliferative ability of basal progenitors (BPs), includingthe basal radial glia and basal intermediate progenitors (bIPs) in mammalian cortex, which may have been acquiredthrough epigenetic alterations in BPs. However, how the epigenome in BPs differs across species is not known.Here, we report that histone H3 acetylation is a key epigenetic regulation in bIP amplification and cortical expansion.Through epigenetic profiling of sorted bIPs, we show that histone H3 lysine 9 acetylation (H3K9ac) is low inmurine bIPs and high in human bIPs. Elevated H3K9ac preferentially increases bIP proliferation, increasing the sizeand folding of the normally smooth mouse neocortex. H3K9ac drives bIP amplification by increasing expressionof the evolutionarily regulated gene, Trnp1, in developing cortex. Our findings demonstrate a previously unknownmechanism that controls cortical architecture.

Loss of BAF Complex in Developing Cortex Perturbs Radial Neuronal Migration in a WNT Signaling-Dependent Manner.
Godwin Sokpor, Cemil Kerimoglu, Huong Nguyen, Linh Pham, Joachim Rosenbusch, Robin Wagener, Huu Phuc Nguy, Andre Fischer, Jochen F. Staiger and Tran Tuoc.
Front. Mol. Neurosci., 16 June 2021 | https://doi.org/10.3389/fnmol.2021.687581, 2021.
abstract link

Radial neuronal migration is a key neurodevelopmental event indispensable for proper cortical laminar organization. Cortical neurons mainly use glial fiber guides, cell adhesion dynamics, and cytoskeletal remodeling, among other discrete processes, to radially trek from their birthplace to final layer positions. Dysregulated radial migration can engender cortical mis-lamination, leading to neurodevelopmental disorders. Epigenetic factors, including chromatin remodelers have emerged as formidable regulators of corticogenesis. Notably, the chromatin remodeler BAF complex has been shown to regulate several aspects of cortical histogenesis. Nonetheless, our understanding of how BAF complex regulates neuronal migration is limited. Here, we report that BAF complex is required for neuron migration during cortical development. Ablation of BAF complex in the developing mouse cortex caused alteration in the cortical gene expression program, leading to loss of radial migration-related factors critical for proper cortical layer formation. Of note, BAF complex inactivation in cortex caused defective neuronal polarization resulting in diminished multipolar-to-bipolar transition and eventual disruption of radial migration of cortical neurons. The abnormal radial migration and cortical mis-lamination can be partly rescued by downregulating WNT signaling hyperactivity in the BAF complex mutant cortex. By implication, the BAF complex modulates WNT signaling to establish the gene expression program required for glial fiber-dependent neuronal migration, and cortical lamination. Overall, BAF complex has been identified to be crucial for cortical morphogenesis through instructing multiple aspects of radial neuronal migration in a WNT signaling-dependent manner.

Post-transcriptional regulation by the exosome complex is required for cell survival and forebrain development via repression of P53 signaling.
Pauline Antonie Ulmke, Yuanbin Xie, Godwin Sokpor, Linh Pham, Orr Shomroni, Tea Berulava, Joachim Rosenbusch, Uttiya Basu, Andre Fischer, Huu Phuc Nguyen, Jochen F. Staiger, Tran Tuoc.
Development 2021 148: dev188276 doi: 10.1242/dev.188276, 2021.
abstract link

Fine-tuned gene expression is crucial for neurodevelopment. The gene expression program is tightly controlled at different levels, including RNA decay. N6-methyladenosine (m6A) methylation-mediated degradation of RNA is essential for brain development. However, m6A methylation impacts not only RNA stability, but also other RNA metabolism processes. How RNA decay contributes to brain development is largely unknown. Here, we show that Exosc10, a RNA exonuclease subunit of the RNA exosome complex, is indispensable for forebrain development. We report that cortical cells undergo overt apoptosis, culminating in cortical agenesis upon conditional deletion of Exosc10 in mouse cortex. Mechanistically, Exosc10 directly binds and degrades transcripts of the P53 signaling-related genes, such as Aen and Bbc3. Overall, our findings suggest a crucial role for Exosc10 in suppressing the P53 pathway, in which the rapid turnover of the apoptosis effectors Aen and Bbc3 mRNAs is essential for cell survival and normal cortical histogenesis.

2018

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.

2016

mSWI/SNF (BAF) complexes are indispensable for the neurogenesis and development of embryonic olfactory epithelium.
Bachmann C*, Nguyen H*, Rosenbusch J*, Pham L, Rabe T, Patwa M, Sokpor G, Seong RH, Ashery-Padan R, Mansouri A, Stoykova A, Staiger JF, Tuoc T..
Plos Genetics, 2016. 12(9), *equally contributed authors
abstract link

Neurogenesis is a key developmental event through which neurons are generated from neural stem/progenitor cells. Chromatin remodeling BAF (mSWI/SNF) complexes have been reported to play essential roles in the neurogenesis of the central nervous system. However, whether BAF complexes are required for neuron generation in the olfactory system is unknown. Here, we identified onscBAF and ornBAF complexes, which are specifically present in olfactory neural stem cells (oNSCs) and olfactory receptor neurons (ORNs), respectively. We demonstrated that BAF155 subunit is highly expressed in both oNSCs and ORNs, whereas high expression of BAF170 subunit is observed only in ORNs. We report that conditional deletion of BAF155, a core subunit in both onscBAF and ornBAF complexes, causes impaired proliferation of oNSCs as well as defective maturation and axonogenesis of ORNs in the developing olfactory epithelium (OE), while the high expression of BAF170 is important for maturation of ORNs. Interestingly, in the absence of BAF complexes in BAF155/BAF170 double-conditional knockout mice (dcKO), OE is not specified. Mechanistically, BAF complex is required for normal activation of Pax6-dependent transcriptional activity in stem cells/progenitors of the OE. Our findings unveil a novel mechanism mediated by the mSWI/SNF complex in OE neurogenesis and development.

Ablation of BAF170 in Developing and Postnatal Dentate Gyrus Affects Neural Stem Cell Proliferation, Differentiation, and Learning.
Tuoc T, Dere E, Radyushkin K, Pham L, Nguyen H, Tonchev AB, Sun G, Ronnenberg A, Shi Y, Staiger JF, Ehrenreich H, Stoykova A.
Molecular Neurobiology, 2016. doi:10.1007/s12035-016-9948-5
abstract link

The BAF chromatin remodeling complex plays an essential role in brain development. However its function in postnatal neurogenesis in hippocampus is still unknown. Here, we show that in postnatal dentate gyrus (DG), the BAF170 subunit of the complex is expressed in radial glial-like (RGL) progenitors and in cell types involved in subsequent steps of adult neurogenesis including mature astrocytes. Conditional deletion of BAF170 during cortical late neurogenesis as well as during adult brain neurogenesis depletes the pool of RGL cells in DG, and promotes terminal astrocyte differentiation. These derangements are accompanied by distinct behavioral deficits, as reflected by an impaired accuracy of place responding in the Morris water maze test, during both hidden platform as well as reversal learning. Inducible deletion of BAF170 in DG during adult brain neurogenesis resulted in mild spatial learning deficits, having a more pronounced effect on spatial learning during the reversal test. These findings demonstrate involvement of BAF170-dependent chromatin remodeling in hippocampal neurogenesis and cognition and suggest a specific role of adult neurogenesis in DG in adaptive behavior.

Epigenetic regulation by BAF (mSWI/SNF) chromatin remodeling complexes is indispensable for embryonic development.
Nguyen H*, Sokpor G*, Pham L, Rosenbusch J, Stoykova A, Staiger JF, Tuoc T.
Cell Cycle, 2016. 2016, 18;15(10):1317-24, equally contributed authors
abstract link

The multi-subunit chromatin-remodeling SWI/SNF (known as BAF for Brg/Brm-associated factor) complexes play essential roles in development. Studies have shown that the loss of individual BAF subunits often affects local chromatin structure and specific transcriptional programs. However, we do not fully understand how BAF complexes function in development because no animal mutant had been engineered to lack entire multi-subunit BAF complexes. Importantly, we recently reported that double conditional knock-out (dcKO) of the BAF155 and BAF170 core subunits in mice abolished the presence of the other BAF subunits in the developing cortex. The generated dcKO mutant provides a novel and powerful tool for investigating how entire BAF complexes affect cortical development. Using this model, we found that BAF complexes globally control the key heterochromatin marks, H3K27me2 and -3, by directly modulating the enzymatic activity of the H3K27 demethylases, Utx and Jmjd3. Here, we present further insights into how the scaffolding ability of the BAF155 and BAF170 core subunits maintains the stability of BAF complexes in the forebrain and throughout the embryo during development. Furthermore, we show that the loss of BAF complexes in the above-described model up-regulates H3K27me3 and impairs forebrain development and embryogenesis. These findings improve our understanding of epigenetic mechanisms and their modulation by the chromatin-remodeling SWI/SNF complexes that control embryonic development.