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The  Sox2  transcription factor must be robustly transcribed in embryonic stem (ES) cells to maintain pluripotency. Two gene-proximal enhancers,  Sox2  regulatory region 1 (SRR1) and SRR2, display activity in reporter assays, but deleting SRR1 has no effect on pluripotency. We identified and functionally validated the sequences required for  Sox2  transcription based on a computational model that predicted transcriptional enhancer elements within 130 kb of  Sox2 . Our reporter assays revealed three novel enhancers—SRR18, SRR107, and SRR111—that, through the formation of chromatin loops, form a chromatin complex with the  Sox2  promoter in ES cells. Using the CRISPR/Cas9 system and F1 ES cells ( Mus musculus  129  ×  Mus castaneus ), we generated heterozygous deletions of each enhancer region, revealing that only the distal cluster containing SRR107 and SRR111, located &gt;100 kb downstream from  Sox2 , is required for  cis -regulation of  Sox2  in ES cells. Furthermore, homozygous deletion of this distal  Sox2  control region (SCR) caused significant reduction in  Sox2  mRNA and protein levels, loss of ES cell colony morphology, genome-wide changes in gene expression, and impaired neuroectodermal formation upon spontaneous differentiation to embryoid bodies. Together, these data identify a distal control region essential for  Sox2  transcription in ES cells.

A Sox2 distal enhancer cluster regulates embryonic stem cell differentiation potential