THAP1: Role in Mouse Embryonic Stem Cell Survival and Differentiation

Stem Cell Reports. 2017 Jul 11;9(1):92-107. doi: 10.1016/j.stemcr.2017.04.032. Epub 2017 Jun 1.

Abstract

THAP1 (THAP [Thanatos-associated protein] domain-containing, apoptosis-associated protein 1) is a ubiquitously expressed member of a family of transcription factors with highly conserved DNA-binding and protein-interacting regions. Mutations in THAP1 cause dystonia, DYT6, a neurologic movement disorder. THAP1 downstream targets and the mechanism via which it causes dystonia are largely unknown. Here, we show that wild-type THAP1 regulates embryonic stem cell (ESC) potential, survival, and proliferation. Our findings identify THAP1 as an essential factor underlying mouse ESC survival and to some extent, differentiation, particularly neuroectodermal. Loss of THAP1 or replacement with a disease-causing mutation results in an enhanced rate of cell death, prolongs Nanog, Prdm14, and/or Rex1 expression upon differentiation, and results in failure to upregulate ectodermal genes. ChIP-Seq reveals that these activities are likely due in part to indirect regulation of gene expression.

Keywords: THAP1; Thanatos-associated protein domain-containing apoptosis-associated protein 1; apoptosis; differentiation; dystonia; embryonic stem cells; neuroectodermal differentiation; survival; transcriptomics; zinc finger transcription factor.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis
  • Cell Differentiation*
  • Cell Line
  • Cell Proliferation
  • Cell Survival*
  • DNA-Binding Proteins / genetics
  • DNA-Binding Proteins / metabolism*
  • Dystonia / genetics
  • Dystonia / metabolism
  • Gene Expression Regulation, Developmental
  • Mice
  • Mouse Embryonic Stem Cells / cytology*
  • Mouse Embryonic Stem Cells / metabolism
  • Mutation

Substances

  • DNA-Binding Proteins
  • THAP1 protein, mouse