https://research-explorer.app.ist.ac.at/download/7957/8805/2020_TrendsNeuroscience_Parenti.pdf

Neurodevelopmental Disorders: From Genetics to Functional Pathways.

The ATP-dependent chromatin remodelling complex BAF (= mammalian SWI/SNF complex) is crucial for the regulation of gene expression and differentiation. In the course of evolution from yeast to mammals, the BAF complex evolved an immense complexity with a high number of subunits encoded by gene families. In this way, tissue-specific BAF function and regulation of development begin with the combinatorial assembly of distinct BAF complexes such as esBAF, npBAF and nBAF. Furthermore, whole-genome sequencing reveals the tremendous role BAF complex mutations have in both neurodevelopmental disorders and human malignancies. Therefore, gaining a more elaborate insight into how BAF complex assembly influences its function and which role distinct subunits play, will hopefully give rise to a better understanding of disease pathogenesis and ultimately to new treatments for many human diseases.

/pdf/the-baf-complex-in-development-and-disease-36q2fjhirr.pdf

The BAF complex in development and disease

The Trithorax group (TrxG) of proteins is a large family of epigenetic regulators that form multiprotein complexes to counteract repressive developmental gene expression programmes established by the Polycomb group of proteins and to promote and maintain an active state of gene expression. Recent studies are providing new insights into how two crucial families of the TrxG — the COMPASS family of histone H3 lysine 4 methyltransferases and the SWI/SNF family of chromatin remodelling complexes — regulate gene expression and developmental programmes, and how misregulation of their activities through genetic abnormalities leads to pathologies such as developmental disorders and malignancies. In this Review, Cenik and Shilatifard focus on two families of Trithorax group proteins: COMPASS histone H3 lysine 4 methyltransferase complexes and SWI/SNF chromatin remodelling complexes. They discuss the roles of these complexes in gene regulation, development and disease.

COMPASS and SWI/SNF complexes in development and disease.

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.

/pdf/chromatin-remodeling-baf-swi-snf-complexes-in-neural-52v3fp342h.pdf

Chromatin Remodeling BAF (SWI/SNF) Complexes in Neural Development and Disorders.

During embryonic brain development, neural progenitor/stem cells (NPCs) sequentially give rise to different subtypes of neurons and glia via a highly orchestrated process. To accomplish the ordered generation of distinct progenies, NPCs go through multistep transitions of their developmental competence. The molecular mechanisms driving precise temporal coordination of these transitions remains enigmatic. Epigenetic regulation, including changes in chromatin structures, DNA methylation, and histone modifications, has been extensively investigated in the context of cortical neurogenesis. Recent studies of chemical modifications on RNA, termed epitranscriptomics, have also revealed their critical roles in neural development. In this review, we discuss advances in understanding molecular regulation of the sequential lineage specification of NPCs in the embryonic mammalian brain with a focus on epigenetic and epitranscriptomic mechanisms. In particular, the discovery of lineage-specific gene transcripts undergoing rapid turnover in NPCs suggests that NPC developmental fate competence is determined much earlier, before the final cell division, and is more tightly controlled than previously appreciated. We discuss how multiple regulatory systems work in harmony to coordinate NPC behavior and summarize recent findings in the context of a model of epigenetic and transcriptional prepatterning to explain NPC developmental competence.

/pdf/epigenetics-and-epitranscriptomics-in-temporal-patterning-of-16d5w2bmg5.pdf

Epigenetics and epitranscriptomics in temporal patterning of cortical neural progenitor competence

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.

/pdf/mswi-snf-baf-complexes-are-indispensable-for-the-sl8yeaf5oq.pdf

mSWI/SNF (BAF) Complexes Are Indispensable for the Neurogenesis and Development of Embryonic Olfactory Epithelium

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mSWI/SNF (BAF) Complexes Are Indispensable for the Neurogenesis and Development of Embryonic Olfactory Epithelium