Stem cell fate choices are regulated through antagonistic control of lysosomes by MYC and TFEB [RNA-Seq 2]

We show that lysosomes are antagonistically controlled by TFEB and MYC to balance catabolic and anabolic processes required for activating LT-HSC and guiding their lineage fate. TFEB-mediated induction of the endolysosomal pathway for membrane receptor degradation limits LT-HSC metabolic and mitogenic activation; this promotes quiescence and self-renewal and governs erythroid-myeloid commitment. By contrast, MYC engages biosynthetic processes while repressing lysosomal catabolism to drive LT-HSC activation. Collectively, our study identifies lysosomes as a central regulatory hub for proper and coordinated stem cell fate determination. Long-term hematopoietic stem cells (LT-HSC) were sorted from human cord blood and cultured overnight before transduction with lentiviral vectors overexpressing an shRNA against Renilla (shCTRL) or TFEB (shTFEB). Six days later, mCherry+ transduced cells were sorted for RNA extraction and sequencing. Authors state that raw data will be uploaded to the EGA database.

本研究表明，溶酶体（lysosomes）受转录因子EB（TFEB）与MYC的拮抗调控，以平衡激活长期造血干细胞（long-term hematopoietic stem cells，LT-HSC）并指导其谱系命运所需的分解代谢与合成代谢过程。由TFEB介导的内体溶酶体通路诱导膜受体降解，可抑制LT-HSC的代谢与有丝分裂原激活过程，进而促进其静息状态与自我更新，并调控红系-髓系定向分化。与之相反，MYC可在抑制溶酶体分解代谢的同时参与合成代谢过程，从而驱动LT-HSC的激活。综上，本研究证实溶酶体是精准协调干细胞命运决定的核心调控枢纽。实验中，研究人员从人脐带血中分离得到长期造血干细胞（LT-HSC），经过夜体外培养后，使用携带过表达靶向海肾（Renilla）的短发夹RNA（shCTRL）或靶向TFEB的短发夹RNA（shTFEB）的慢病毒载体进行转导。转导6天后，分选得到mCherry阳性的转导细胞，用于RNA提取与测序。作者声明，原始数据将上传至欧洲基因组表型档案数据库（EGA）。