DBC1, p300, HDAC3, and Siah1 coordinately regulate ELL stability and function for expression of its target genes

Proc Natl Acad Sci U S A. 2020 Mar 24;117(12):6509-6520. doi: 10.1073/pnas.1912375117. Epub 2020 Mar 9.

Abstract

Among all of the Super Elongation Complex (SEC) components, ELL1 (also known as ELL) is the only bona fide elongation factor that directly stimulates transcription elongation by RNA polymerase II. However, the mechanism(s) of functional regulation of ELL1 (referred to as ELL hereafter), through its stabilization, is completely unknown. Here, we report a function of human DBC1 in regulating ELL stability involving HDAC3, p300, and Siah1. Mechanistically, we show that p300-mediated site-specific acetylation increases, whereas HDAC3-mediated deacetylation decreases, ELL stability through polyubiquitylation by the E3 ubiquitin ligase Siah1. DBC1 competes with HDAC3 for the same binding sites on ELL and thus increases its acetylation and stability. Knockdown of DBC1 reduces ELL levels and expression of a significant number of genes, including those involved in glucose metabolism. Consistently, Type 2 diabetes patient-derived peripheral blood mononuclear cells show reduced expression of DBC1 and ELL and associated key target genes required for glucose homeostasis. Thus, we describe a pathway of regulating stability and functions of key elongation factor ELL for expression of diverse sets of genes, including ones that are linked to Type 2 diabetes pathogenesis.

Keywords: DBC1; ELL; acetylation; transcription; ubiquitylation.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acetylation
  • Adaptor Proteins, Signal Transducing / genetics
  • Adaptor Proteins, Signal Transducing / metabolism*
  • Animals
  • Binding Sites
  • Cell Line
  • Diabetes Mellitus, Type 2 / pathology
  • E1A-Associated p300 Protein / genetics
  • E1A-Associated p300 Protein / metabolism*
  • Gene Expression Regulation*
  • Gene Knockdown Techniques
  • Glucose / metabolism
  • Histone Deacetylases / genetics
  • Histone Deacetylases / metabolism*
  • Humans
  • Leukocytes, Mononuclear / metabolism
  • Mutation
  • Nuclear Proteins / metabolism*
  • Protein Binding
  • Protein Stability
  • Transcription, Genetic
  • Transcriptional Elongation Factors / chemistry
  • Transcriptional Elongation Factors / genetics
  • Transcriptional Elongation Factors / metabolism*
  • Ubiquitin-Protein Ligases / metabolism*
  • Ubiquitination

Substances

  • Adaptor Proteins, Signal Transducing
  • CCAR2 protein, human
  • ELL protein, human
  • Nuclear Proteins
  • Transcriptional Elongation Factors
  • E1A-Associated p300 Protein
  • EP300 protein, human
  • Ubiquitin-Protein Ligases
  • seven in absentia proteins
  • Histone Deacetylases
  • histone deacetylase 3
  • Glucose