Characterization of Sox15 binding occupancy and gene expression (ChIP-Seq)

SOX15 and SOX2 are Sox family transcription factors (TFs) enriched in embryonic stem cells (ESCs). The role of SOX2 in activating gene expression programs essential for stem cell self-renewal and acquisition of pluripotency in somatic cells during reprogramming is well-documented. However, the contribution of SOX15 to these processes is unclear and often presumed redundant with SOX2 because both TFs display similar DNA binding specificity. Here, we show that SOX15 contributes to stem cell maintenance by cooperating with ESC-enriched transcriptional coactivators to ensure optimal expression of pluripotency-associated genes. We demonstrate that SOX15 depletion compromises reprogramming of fibroblasts to pluripotency which cannot be compensated by SOX2. Ectopic expression of SOX15 promotes the reversion of a more restricted, post-implantation pluripotent state back to a pre-implantation, ESC-like identity even though SOX2 is expressed in both cell states. We also uncover a role of SOX15 in lineage specification, by showing that loss of SOX15 leads to defects in commitment of ESCs to neural fates. SOX15 promotes neural differentiation by binding to and activating a previously uncharacterized distal enhancer of a key neurogenic regulator, Hes5. Together, these findings identify a multifaceted role of SOX15 in induction and maintenance of pluripotency and neural differentiation. We performed ChIP-seq in HA-tagged SOX15 and SOX2 knockin mouse ESCs to identify SOX15 and SOX2 binding sites, respectively. We generated Sox15 knockout mouse ESC lines and anlayzed changes in gene expression by RNA-seq.