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Published on: August 15, 2019
Smarcb1 Loss Results in a Deregulation of esBAF Binding and Impacts the Expression of Neurodevelopmental Genes
Amelie Alfert1, Carolin Walter2, Natalia Moreno1
1Department of Pediatric Hematology and Oncology, University Children's Hospital Münster, 48149 Münster, Germany.
Abstract:
The murine esBAF complex plays a major role in the regulation of gene expression during stem cell development and differentiation. As one of its core subunits, Smarcb1 is indispensable for its function and its loss is connected to neurodevelopmental disorders and participates in the carcinogenesis of entities such as rhabdoid tumours. We explored how Smarcb1 regulates gene programs in murine embryonic stem cells (mESC) and in this way orchestrates differentiation. Our data underline the importance of Smarcb1 expression and function for the development of the nervous system along with basic cellular functions, such as cell adhesion and cell organisation. Using ChIP-seq, we were able to portray the consequences of Smarcb1 knockdown (kd) for the binding of esBAF and PRC2 as well as its influence on histone marks H3K27me3, H3K4me3 and H3K27ac. Their signals are changed in gene and enhancer regions of genes connected to nervous system development and offers a plausible explanation for changes in gene expression. Further, we describe a group of genes that are, despite increased BAF binding, suppressed after Smarcb1 kd by mechanisms independent of PRC2 function.
Insights
Smarcb1 is crucial for embryonic stem cell differentiation and nervous system development. Its loss impacts gene regulation, cell organization, and histone modifications, affecting neural development and potentially contributing to cancers.
Area of Science:
- Molecular Biology
- Developmental Biology
- Epigenetics
Background:
- The esBAF complex is vital for gene expression in stem cells.
- Smarcb1, a core subunit, is essential for esBAF function.
- Smarcb1 loss is linked to neurodevelopmental disorders and rhabdoid tumors.
Purpose of the Study:
- Investigate Smarcb1's role in regulating gene programs during murine embryonic stem cell differentiation.
- Elucidate Smarcb1's impact on nervous system development and cellular functions.
Main Methods:
- ChIP-sequencing (ChIP-seq) to analyze Smarcb1 knockdown effects.
- Assessed binding of esBAF and PRC2 complexes.
- Examined histone modifications (H3K27me3, H3K4me3, H3K27ac) at gene and enhancer regions.
Main Results:
- Smarcb1 knockdown altered esBAF and PRC2 binding and key histone marks.
- Changes were observed in genes related to nervous system development.
- Identified PRC2-independent gene suppression mechanisms following Smarcb1 knockdown.
Conclusions:
- Smarcb1 is critical for nervous system development and cellular organization.
- Smarcb1 influences gene expression via epigenetic modifications.
- Smarcb1's function is essential for maintaining normal cellular processes and development.
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