Discovery of Novel Human Gene Regulatory Modules from Gene Co-expression and Promoter Motif Analysis

Sci Rep. 2017 Jul 17;7(1):5557. doi: 10.1038/s41598-017-05705-2.

Abstract

Deciphering gene regulatory networks requires identification of gene expression modules. We describe a novel bottom-up approach to identify gene modules regulated by cis-regulatory motifs from a human gene co-expression network. Target genes of a cis-regulatory motif were identified from the network via the motif's enrichment or biased distribution towards transcription start sites in the promoters of co-expressed genes. A gene sub-network containing the target genes was extracted and used to derive gene modules. The analysis revealed known and novel gene modules regulated by the NF-Y motif. The binding of NF-Y proteins to these modules' gene promoters were verified using ENCODE ChIP-Seq data. The analyses also identified 8,048 Sp1 motif target genes, interestingly many of which were not detected by ENCODE ChIP-Seq. These target genes assemble into house-keeping, tissues-specific developmental, and immune response modules. Integration of Sp1 modules with genomic and epigenomic data indicates epigenetic control of Sp1 targets' expression in a cell/tissue specific manner. Finally, known and novel target genes and modules regulated by the YY1, RFX1, IRF1, and 34 other motifs were also identified. The study described here provides a valuable resource to understand transcriptional regulation of various human developmental, disease, or immunity pathways.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • CCAAT-Binding Factor / genetics
  • Epigenesis, Genetic*
  • Gene Expression Regulation
  • Gene Regulatory Networks*
  • Humans
  • Interferon Regulatory Factor-1 / genetics
  • Lysine / metabolism
  • Methylation
  • Nucleotide Motifs
  • Oligonucleotide Array Sequence Analysis
  • Promoter Regions, Genetic*
  • Regulatory Factor X1 / genetics
  • Sp1 Transcription Factor / genetics
  • YY1 Transcription Factor / genetics

Substances

  • CCAAT-Binding Factor
  • IRF1 protein, human
  • Interferon Regulatory Factor-1
  • RFX1 protein, human
  • Regulatory Factor X1
  • Sp1 Transcription Factor
  • SP1 protein, human
  • YY1 Transcription Factor
  • YY1 protein, human
  • Lysine