Hairy-related transcription factors inhibit GATA-dependent cardiac gene expression through a signal-responsive mechanism

Irfan S. Kathiriya, Isabelle N. King, Masao Murakami, Masayo Nakagawa, John M. Astle, Kelly A. Gardner, Robert D. Gerard, Eric N. Olson, Deepak Srivastava, Osamu Nakagawa

Research output: Contribution to journalArticle

55 Scopus citations

Abstract

Combinatorial actions of transcription factors in multiprotein complexes dictate gene expression profiles in cardiac development and disease. The Hairy-related transcription factor (HRT) family of basic helix-loop-helix proteins is composed of transcriptional repressors highly expressed in the cardiovascular system. However, it has remained unclear whether HRT proteins modulate gene expression driven by cardiac transcriptional activators. Here, we have shown that HRT proteins inhibit cardiac gene transcription by interfering with GATA transcription factors that are implicated in cardiac development and hypertrophy. HRT proteins inhibited GATA-dependent transcriptional activation of cardiac gene promoters such as the atrial natriuretic factor (ANF) promoter. Adenovirus-mediated expression of Hrt2 suppressed mRNA expression of ANF and other cardiac-specific genes in cultured cardiomyocytes. Among various signaling molecules implicated in cardiomyocyte growth, constitutively active Akt1/protein kinase Bα relieved Hrt2-mediated inhibition of GATA-dependent transcription. HRT proteins physically interacted with GATA proteins, and the basic domain of HRT was critical for physical association as well as transcriptional inhibition. These results suggest that HRT proteins may regulate specific sets of cardiac genes by modulating the function of GATA proteins and other cardiac transcriptional activators in a signal-dependent manner.

Original languageEnglish (US)
Pages (from-to)54937-54943
Number of pages7
JournalJournal of Biological Chemistry
Volume279
Issue number52
DOIs
StatePublished - Dec 24 2004

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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    Kathiriya, I. S., King, I. N., Murakami, M., Nakagawa, M., Astle, J. M., Gardner, K. A., Gerard, R. D., Olson, E. N., Srivastava, D., & Nakagawa, O. (2004). Hairy-related transcription factors inhibit GATA-dependent cardiac gene expression through a signal-responsive mechanism. Journal of Biological Chemistry, 279(52), 54937-54943. https://doi.org/10.1074/jbc.M409879200