SNF5 Is an Essential Executor of Epigenetic Regulation during Differentiation

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Abstract
Nucleosome occupancy controls the accessibility of the transcription machinery to DNA regulatory regions and serves an instructive role for gene expression. Chromatin remodelers, such as the BAF complexes, are responsible for establishing nucleosome occupancy patterns, which are key to epigenetic regulation along with DNA methylation and histone modifications. Some reports have assessed the roles of the BAF complex subunits and stemness in murine embryonic stem cells. However, the details of the relationships between remodelers and transcription factors in altering chromatin configuration, which ultimately affects gene expression during cell differentiation, remain unclear. Here for the first time we demonstrate that SNF5, a core subunit of the BAF complex, negatively regulates OCT4 levels in pluripotent cells and is essential for cell survival during differentiation. SNF5 is responsible for generating nucleosome-depleted regions (NDRs) at the regulatory sites of OCT4 repressed target genes such as PAX6 and NEUROG1, which are crucial for cell fate determination. Concurrently, SNF5 closes the NDRs at the regulatory regions of OCT4-activated target genes such as OCT4 itself and NANOG. Furthermore, using loss- and gain-of-function experiments followed by extensive genome-wide analyses including gene expression microarrays and ChIP-sequencing, we highlight that SNF5 plays dual roles during differentiation by antagonizing the expression of genes that were either activated or repressed by OCT4, respectively. Together, we demonstrate that SNF5 executes the switch between pluripotency and differentiation. DNA is packaged with proteins into higher-order chromatin structures, which makes genes inherently resistant to transcription initiation. The importance of chromatin remodelers in inducing structural changes to chromatin and, therefore, in controlling the expression of genes has recently resurfaced with the realization that several of them are mutated in human cancers. SNF5, which serves as the core subunit of the BAF remodeling complex, is one such remodeler. In this study, we identify the role of SNF5 induced chromatin remodeling in cell differentiation, the commitment of embryonic cells to a mature lineage-committed state. Importantly, we find that SNF5 establishes appropriate chromatin remodeling patterns during differentiation by controlling the levels of the OCT4 protein, the master determinant of the undifferentiated state. On receipt of differentiation cues, SNF5 opens the chromatin of repressed genes that are occupied by OCT4. SNF5 also induces the closing of genes that are being actively transcribed and OCT4 bound. Further, we show that SNF5 is necessary for cell survival during differentiation, highlighting its crucial role in the process. Together, our data shed novel insights on the importance of SNF5 in maintaining the balance between the embryonic and differentiated states.

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