Competition between negative acting YY1 versus positive acting serum response factor and tinman homologue Nkx-2.5 regulates cardiac alpha-actin promoter activity

Mol Endocrinol. 1997 Jun;11(6):812-22. doi: 10.1210/mend.11.6.0015.

Abstract

Transcription of sarcomeric alpha-actin genes is developmentally regulated during skeletal and cardiac muscle development through fine-tuned control mechanisms involving multiple cooperative and antagonistic transcription factors. Among the cis-acting DNA elements recognized by these factors is the sequence CC(A/T)6GG of the serum response element (SRE), which is present in a number of growth factor-inducible and myogenic specified genes. We recently showed that the cardiogenic homeodomain factor, Nkx-2.5, served as a positive acting accessory factor for serum response factor (SRF) and together provided strong transcriptional activation of the cardiac alpha-actin promoter. In addition, Nkx-2.5 and SRF collaborated to activate the endogenous murine cardiac alpha-actin gene in 10T1/2 fibroblasts, by a mechanism that involved coassociation of SRF and Nkx-2.5 on intact SREs of the alpha-actin promoter. Here, we show that the second SRE of the avian cardiac alpha-actin promoter served as a binding site for Nkx-2.5, SRF, and zinc finger containing GLI-Kruppel-like factor, YY1. Expression of YY1 inhibited cardiac alpha-actin promoter activity, whereas coexpression of Nkx-2.5 and SRF was able to partially reverse YY1 repression. Displacement of YY1 binding by Nkx-2.5/SRF complex occurs through mutually exclusive binding across the CaSRE2. The interplay and functional antagonism between YY1 and Nkx-2.5/SRF might constitute a developmental as well as a physiologically regulated mechanism that modulates cardiac alpha-actin gene expression during cardiogenesis.

Publication types

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

MeSH terms

  • Actins / genetics*
  • Animals
  • Cells, Cultured
  • Chickens
  • DNA-Binding Proteins / genetics*
  • Fibroblasts / cytology
  • Gene Expression Regulation
  • Homeobox Protein Nkx-2.5
  • Homeodomain Proteins / genetics*
  • Humans
  • Myocardium / cytology
  • Myocardium / metabolism*
  • Nuclear Proteins / genetics*
  • Promoter Regions, Genetic*
  • Regulatory Sequences, Nucleic Acid
  • Repressor Proteins / genetics*
  • Serum Response Factor
  • Transcription Factors / genetics*
  • Transcriptional Activation*
  • Xenopus Proteins*
  • Zinc Fingers*

Substances

  • Actins
  • DNA-Binding Proteins
  • Homeobox Protein Nkx-2.5
  • Homeodomain Proteins
  • NKX2-5 protein, human
  • Nkx2-5 protein, mouse
  • Nuclear Proteins
  • Repressor Proteins
  • Serum Response Factor
  • Transcription Factors
  • Xenopus Proteins
  • E4f1 protein, mouse