Genetic and epigenetic features of promoters with ubiquitous chromatin accessibility support ubiquitous transcription of cell-essential genes

Nucleic Acids Res. 2021 Jun 4;49(10):5705-5725. doi: 10.1093/nar/gkab345.

Abstract

Gene expression is controlled by regulatory elements within accessible chromatin. Although most regulatory elements are cell type-specific, a subset is accessible in nearly all the 517 human and 94 mouse cell and tissue types assayed by the ENCODE consortium. We systematically analyzed 9000 human and 8000 mouse ubiquitously-accessible candidate cis-regulatory elements (cCREs) with promoter-like signatures (PLSs) from ENCODE, which we denote ubi-PLSs. These are more CpG-rich than non-ubi-PLSs and correspond to genes with ubiquitously high transcription, including a majority of cell-essential genes. ubi-PLSs are enriched with motifs of ubiquitously-expressed transcription factors and preferentially bound by transcriptional cofactors regulating ubiquitously-expressed genes. They are highly conserved between human and mouse at the synteny level but exhibit frequent turnover of motif sites; accordingly, ubi-PLSs show increased variation at their centers compared with flanking regions among the ∼186 thousand human genomes sequenced by the TOPMed project. Finally, ubi-PLSs are enriched in genes implicated in Mendelian diseases, especially diseases broadly impacting most cell types, such as deficiencies in mitochondrial functions. Thus, a set of roughly 9000 mammalian promoters are actively maintained in an accessible state across cell types by a distinct set of transcription factors and cofactors to ensure the transcriptional programs of cell-essential genes.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Amino Acid Motifs
  • Animals
  • Base Composition
  • Chromatin / genetics
  • Chromatin / metabolism*
  • DNA Methylation
  • DNA-Binding Proteins / genetics
  • DNA-Binding Proteins / metabolism
  • Databases, Genetic
  • Epigenesis, Genetic*
  • Epigenomics
  • Gene Expression Regulation / genetics*
  • Gene Ontology
  • Genes, Essential
  • Genome Components
  • Genome, Human
  • Humans
  • Mice
  • Neoplasm Proteins / genetics
  • Neoplasm Proteins / metabolism
  • Nuclear Proteins / genetics
  • Nuclear Proteins / metabolism
  • Organ Specificity / genetics
  • Promoter Regions, Genetic
  • Regulatory Sequences, Nucleic Acid*
  • Repressor Proteins / genetics
  • Repressor Proteins / metabolism
  • TATA Box
  • Transcription Factors / genetics
  • Transcription Factors / metabolism*
  • Transcriptome / genetics*

Substances

  • Chromatin
  • DNA-Binding Proteins
  • EMSY protein, human
  • KMT2C protein, human
  • Neoplasm Proteins
  • Nuclear Proteins
  • Repressor Proteins
  • Transcription Factors