ApoE maintains neuronal integrity via microRNA and H3K27me3-mediated repression
Jiazi Tan,
Yow-Yong Tan,
Zhen-Kai Ngian,
Suet-Yen Chong,
Vinay Kumar Rao,
Jiong-Wei Wang,
Xianmin Zeng,
Chin-Tong Ong
Affiliations
Jiazi Tan
Temasek Life Sciences Laboratory, National University of Singapore, Singapore 117604, Singapore
Yow-Yong Tan
Temasek Life Sciences Laboratory, National University of Singapore, Singapore 117604, Singapore; Department of Biological Sciences, National University of Singapore, Singapore 117543, Singapore
Zhen-Kai Ngian
Temasek Life Sciences Laboratory, National University of Singapore, Singapore 117604, Singapore
Suet-Yen Chong
Department of Surgery, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 119228, Singapore; Cardiovascular Research Institute, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117599, Singapore
Vinay Kumar Rao
Temasek Life Sciences Laboratory, National University of Singapore, Singapore 117604, Singapore; Department of Medical Genetics, JSS Medical College, JSS Academy of Higher Education and Research, Mysore 570015, India
Jiong-Wei Wang
Department of Surgery, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 119228, Singapore; Cardiovascular Research Institute, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117599, Singapore; Nanomedicine Translational Research Programme, Centre for NanoMedicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117609, Singapore; Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117593, Singapore
Xianmin Zeng
Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117593, Singapore; RxCell Inc, Novato, CA 94945, USA
Chin-Tong Ong
Temasek Life Sciences Laboratory, National University of Singapore, Singapore 117604, Singapore; Department of Biological Sciences, National University of Singapore, Singapore 117543, Singapore; Corresponding author
Summary: ApoE regulates neurogenesis, although how it influences genetic programs remains elusive. Cortical neurons induced from isogenic control and ApoE−/− human neural stem cells (NSCs) recapitulated key transcriptomic signatures of in vivo counterparts identified from single-cell human midbrain. Surprisingly, ApoE expression in NSC and neural progenitor cells (NPCs) is not required for differentiation. Instead, ApoE prevents the over-proliferation of non-neuronal cells during extended neuronal culture when it is not expressed. Elevated miR-199a-5p level in ApoE−/− cells lowers the EZH1 protein and the repressive H3K27me3 mark, a phenotype rescued by miR-199a-5p steric inhibitor. Reduced H3K27me3 at genes linked to extracellular matrix organization and angiogenesis in ApoE−/− NPC correlates with their aberrant expression and phenotypes in neurons. Interestingly, the ApoE coding sequence, which contains many predicted miR-199a-5p binding sites, can repress miR-199a-5p without translating into protein. This suggests that ApoE maintains neurons integrity through the target-directed miRNA degradation of miR-199a-5p, imparting the H3K27me3-mediated repression of non-neuronal genes during differentiation.
