Far Upstream Element-Binding Protein 1 Regulates LSD1 Alternative Splicing to Promote Terminal Differentiation of Neural Progenitors

Inah Hwang, Dongqing Cao, Yoonmi Na, Do Yeon Kim, Tuo Zhang, Jun Yao, Hwanhee Oh, Jian Hu, Hongwu Zheng, Yu Yao, Jihye Paik

Research output: Contribution to journalArticlepeer-review

26 Scopus citations

Abstract

Loss of a cell's ability to terminally differentiate because of mutations is a selected genetic event in tumorigenesis. Genomic analyses of low-grade glioma have reported recurrent mutations of far upstream element-binding protein 1 (FUBP1). Here, we show that FUBP1 expression is dynamically regulated during neurogenesis and that its downregulation in neural progenitors impairs terminal differentiation and promotes tumorigenesis collaboratively with expression of IDH1 R132H . Mechanistically, collaborative action between SRRM4 and FUBP1 is necessary for mini-exon splicing of the neurospecific LSD1+8a isoform. LSD1+8a was downregulated upon loss of FUBP1 in neural progenitors, thereby impairing terminal neuronal differentiation and maturation. Reinforcing LSD1+8a expression in FUBP1-downregulated neural progenitors restored terminal differentiation and suppressed tumorigenesis; hence, LSD1+8a is an obligatory effector of FUBP1-dependent neuronal differentiation. These findings establish a direct role for FUBP1 in neuronal differentiation and also explain its tumor-suppressor function in the nervous system. In this article, Paik and colleagues demonstrate that FUBP1 plays an indispensable role in promoting terminal differentiation of neurons and that lack of FUBP1 interferes with early-born neuronal cells exiting the cell cycle and predisposes these cells for transformation. These findings explain how FUBP1 serves uniquely as a tumor suppressor in the CNS.

Original languageEnglish
Pages (from-to)1208-1221
Number of pages14
JournalStem Cell Reports
Volume10
Issue number4
DOIs
StatePublished - 10 Apr 2018

Bibliographical note

Publisher Copyright:
© 2018 The Authors

Keywords

  • FUBP1
  • LSD1
  • differentiation
  • glioma
  • neural stem cell
  • oligodendroglioma
  • splicing

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