Brigham Regenerative Medicine Center, Brigham and Women's Hospital, Boston, Massachusetts, USA; Department of Medicine, Cardiovascular Medicine Division, Harvard Medical School, Boston, Massachusetts, USA; Harvard Stem Cell Institute, Cambridge, Massachusetts, USA.
Department of Molecular and Cell Biology, Li Ka Shing Center for Biomedical and Health Sciences, California Institute for Regenerative Medicine Center of Excellence, University of California at Berkeley, Berkeley, California, USA; Howard Hughes Medical Institute, Berkeley, California, USA.
J Biol Chem. 2023 Mar;299(3):102996. doi: 10.1016/j.jbc.2023.102996. Epub 2023 Feb 9.
SOX2 and SOX15 are Sox family transcription factors 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 during somatic cell reprogramming is well-documented. However, the contribution of SOX15 to these processes is unclear and often presumed redundant with SOX2 largely because overexpression of SOX15 can partially restore self-renewal in SOX2-deficient ESCs. 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 postimplantation, epiblast stem cell state back to a preimplantation, 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.
SOX2 和 SOX15 是 Sox 家族转录因子，在胚胎干细胞 (ESCs) 中丰富表达。SOX2 在激活基因表达程序方面的作用对于体细胞重编程过程中干细胞自我更新和获得多能性至关重要，这一作用已得到充分证实。然而，SOX15 在这些过程中的贡献尚不清楚，并且通常被认为与 SOX2 冗余，主要是因为 SOX15 的过表达可以部分恢复 SOX2 缺陷的 ESCs 的自我更新。在这里，我们表明 SOX15 通过与 ESC 丰富的转录共激活因子合作，有助于维持干细胞，以确保多能性相关基因的最佳表达。我们证明 SOX15 的耗竭会损害成纤维细胞向多能性的重编程，而这不能被 SOX2 补偿。SOX15 的异位表达促进了植入后胚胎干细胞状态向植入前 ESC 样状态的逆转，尽管 SOX2 在这两种细胞状态中都表达。我们还揭示了 SOX15 在谱系特化中的作用，表明 SOX15 的缺失导致 ESCs 向神经命运的分化缺陷。SOX15 通过与关键神经发生调节剂 Hes5 的一个以前未被表征的远端增强子结合并激活，促进神经分化。总之，这些发现确定了 SOX15 在诱导和维持多能性和神经分化中的多方面作用。
