Curriculum Vitae

Publications

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.

Molecular Profiling Reveals Involvement of ESCO2 in Intermediate Progenitor Cell Maintenance in the Developing Mouse Cortex.
Pauline Antonie Ulmke, M Sadman Sakib, Peter Ditte, Godwin Sokpor, Cemil Kerimoglu, Linh Pham, Yuanbin Xie, Xiaoyi Mao, Joachim Rosenbusch, Ulrike Teichmann, Huu Phuc Nguyen, Andre Fischer, Gregor Eichele, Jochen F Staiger, Tran Tuoc.
Stem Cell Reports 2021 Apr 13;16(4):968-984, 2021.
abstract link

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.

2019

RBM15 Modulates the Function of Chromatin Remodeling Factor BAF155 Through RNA Methylation in Developing Cortex.
Xie Y*, Hernandez RC*, Sokpor G, Pham L, Narayanan R, Rosenbusch J, Staiger JF, Tuoc T.
Molecular Neurobiology, https://doi.org/10.1007/s12035-019-1595-1, 2019.
abstract link

Chromatin remodeling factor BAF155 is an important regulator of many biological processes. As a core and scaffold subunit of the BAF (SWI/SNF-like) complex, BAF155 is capable of regulating the stability and function of the BAF complex. The spatiotemporal expression of BAF155 during embryogenesis is essential for various aspects of organogenesis, particularly in the brain development. However, our understanding of the mechanisms that regulate the expression and function of BAF155 is limited. Here, we report that RBM15, a subunit of the m6A methyltransferase complex, interacts with BAF155 mRNA and mediates BAF155 mRNA degradation through the mRNA methylation machinery. Ablation of endogenous RBM15 expression in cultured neuronal cells and in the developing cortex augmented the expression of BAF155. Conversely, RBM15 overexpression decreased BAF155 mRNA and protein levels, and perturbed BAF155 functions in vivo, including repression of BAF155-dependent transcriptional activity and delamination of apical radial glial progenitors as a hallmark of basal radial glial progenitor genesis. Furthermore, we demonstrated that the regulation of BAF155 by RBM15 depends on the activity of the mRNA methylation complex core catalytic subunit METTL3. Altogether, our findings reveal a new regulatory avenue that elucidates how BAF complex subunit stoichiometry and functional modulation are achieved in mammalian cells.

2017

Chromatin Remodeling BAF (SWI/SNF) Complexes in Neural Development and Disorders.
Sokpor G*, Xie Y*, Rosenbusch J, Tuoc T.
Front. Mol. Neurosci. | doi: 10.3389/fnmol.2017.00243 , 2017.
abstract link

The ATP-dependent BRG1/BRM associated factor (BAF) chromatin remodeling complexes are crucial in regulating gene expression by controlling chromatin dynamics. Over the last decade, it has become increasingly clear that during neural development in mammals, distinct ontogenetic stage-specific BAF complexes derived from combinatorial assembly of their subunits are formed in neural progenitors and post-mitotic neural cells. Proper functioning of the BAF complexes plays critical roles in neural development, including the establishment and maintenance of neural fates and functionality. Indeed, recent human exome sequencing and genome-wide association studies have revealed that mutations in BAF complex subunits are linked to neurodevelopmental disorders such as Coffin-Siris syndrome, Nicolaides-Baraitser syndrome, Kleefstra’s syndrome spectrum, Hirschsprung’s disease, autism spectrum disorder, and schizophrenia. In this review, we focus on the latest insights into the functions of BAF complexes during neural development and the plausible mechanistic basis of how mutations in known BAF subunits are associated with certain neurodevelopmental disorders.

2012

Unique functional properties of somatostatin-expressing GABAergic neurons in mouse barrel cortex.
Gentet LJ, Kremer Y, Taniguchi H, Huang ZJ, Staiger J, Petersen CCH.
Nat Neurosci 15:607-612, 2012.
abstract link

Neocortical GABAergic neurons have diverse molecular, structural and electrophysiological features, but the functional correlates of this diversity are largely unknown. We found unique membrane potential dynamics of somatostatin-expressing (SOM) neurons in layer 2/3 of the primary somatosensory barrel cortex of awake behaving mice. SOM neurons were spontaneously active during periods of quiet wakefulness. However, SOM neurons hyperpolarized and reduced action potential firing in response to both passive and active whisker sensing, in contrast with all other recorded types of nearby neurons, which were excited by sensory input. Optogenetic inhibition of SOM neurons increased burst firing in nearby excitatory neurons. We hypothesize that the spontaneous activity of SOM neurons during quiet wakefulness provides a tonic inhibition to the distal dendrites of excitatory pyramidal neurons. Conversely, the inhibition of SOM cells during active cortical processing likely enhances distal dendritic excitability, which may be important for top-down computations and sensorimotor integration.