Bookmarking by Non-pioneer Transcription Factors during Liver Development Establishes Competence for Future Gene Activation

Cell Rep. 2020 Feb 4;30(5):1319-1328.e6. doi: 10.1016/j.celrep.2020.01.006.


Transcription factor binding to enhancer and promoter regions critical for homeostatic adult gene activation is established during development. To understand how cell-specific gene expression patterns are generated, we study the developmental timing of association of two prominent hepatic transcription factors with gene regulatory regions. Most individual binding events display extraordinarily high temporal variations during liver development. Early and persistent binding is necessary, but not sufficient, for gene activation. Stable gene expression patterns are the result of combinatorial activity of multiple transcription factors, which mark regulatory regions long before activation and promote progressive broadening of active chromatin domains. Both temporally stable and dynamic, short-lived binding events contribute to the developmental maturation of active promoter configurations. The results reveal a developmental bookmarking function of master regulators and illuminate remarkable parallels between the principles employed for gene activation during development, during evolution, and upon mitotic exit.

Keywords: CEBP; HNF4; chromatin; development; gene regulation; liver; transcription factor.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • CCAAT-Enhancer-Binding Protein-beta / genetics
  • CCAAT-Enhancer-Binding Protein-beta / metabolism
  • Chromatin / metabolism
  • Gene Expression Regulation, Developmental
  • Gene Silencing
  • Hepatocyte Nuclear Factor 4 / metabolism
  • Humans
  • Liver / embryology*
  • Liver / metabolism*
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Protein Binding
  • Regulatory Sequences, Nucleic Acid
  • Transcription Factors / metabolism*
  • Transcriptional Activation / genetics*


  • CCAAT-Enhancer-Binding Protein-beta
  • Cebpb protein, mouse
  • Chromatin
  • Hepatocyte Nuclear Factor 4
  • Hnf4a protein, mouse
  • Transcription Factors