SOX2 can associate with chromatin directly by binding to DNA or indirectly via association with other chromatin-bound proteins
It is widely assumed that SOX2 regulates gene expression and facilitates the opening of chromatin by binding directly at SOX motifs. To test this assumption, we created a SOX2 DNA binding mutant to determine whether other regions of SOX2 contribute to gene target specificity. When exogenously expressed in cells, this SOX2 mutant [SOX2(G76P)], like elevated unmodified SOX2, dramatically alters the…
SOX2 is known to regulate gene expression and open chromatin through direct binding to SOX motifs. To explore this assumption further, researchers engineered a SOX2 mutant (SOX2(G76P)) that lacked its DNA binding domain. When expressed in cells, this mutant significantly altered the transcriptome, but with different gene sets and networks compared to unmodified SOX2.
ChIP-seq analysis revealed that SOX2 and SOX2(G76P) primarily associate with distinct genomic regions. Motif analysis showed that SOX2 binds mainly to SOX motifs, while SOX2(G76P) attaches to non-SOX motifs, including AP-1 motifs. ATAC-seq analysis demonstrated that SOX2 enhances chromatin accessibility, but SOX2(G76P) does not.
The researchers concluded that SOX2(G76P) indirectly associates with chromatin via a "piggyback" mechanism, through its connection with other chromatin-associated proteins, such as AP-1 complexes. Intriguingly, both SOX2 and SOX2(G76P) share some gene loci containing multiple DNA motifs, including AP-1 motifs, but not strong SOX motifs.
The findings propose two key insights: SOX2's gene target selection is not solely driven by its DNA binding domain, and the protein can also bind to certain gene loci indirectly by linking with other chromatin-associated proteins.
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