Hairy-related transcription factors inhibit GATA-dependent cardiac gene expression through a signal-responsive mechanism.
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 B alpha 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.
Kathiriya
Irfan S
IS
Department of Molecular Biology, The University of Texas Southwestern Medical Center, Dallas, Texas 75390-9148, USA.
King
Isabelle N
IN
Murakami
Masao
M
Nakagawa
Masayo
M
Astle
John M
JM
Gardner
Kelly A
KA
Gerard
Robert D
RD
Olson
Eric N
EN
Srivastava
Deepak
D
Nakagawa
Osamu
O
D000818:Animals; D009320:Atrial Natriuretic Factor / Q000235:genetics; D051792:Basic Helix-Loop-Helix Proteins; D019556:COS Cells; D006332:Cardiomegaly; D002478:Cells, Cultured; D002522:Chlorocebus aethiops; D004268:DNA-Binding Proteins / Q000235:genetics / Q000502:physiology*; D050991:GATA4 Transcription Factor; D017353:Gene Deletion; D015870:Gene Expression / Q000187:drug effects / Q000502:physiology*; D018257:Helix-Loop-Helix Motifs; D006801:Humans; D008156:Luciferases / Q000235:genetics; D051379:Mice; D032383:Myocytes, Cardiac / Q000737:chemistry / Q000378:metabolism*; D011401:Promoter Regions, Genetic / Q000235:genetics; D017346:Protein Serine-Threonine Kinases / Q000502:physiology; D011518:Proto-Oncogene Proteins / Q000502:physiology; D051057:Proto-Oncogene Proteins c-akt; D012333:RNA, Messenger / Q000032:analysis; D051381:Rats; D011993:Recombinant Fusion Proteins; D012097:Repressor Proteins / Q000235:genetics / Q000502:physiology*; D015398:Signal Transduction; D014157:Transcription Factors / Q000235:genetics / Q000502:physiology*; D014162:Transfection
D009320:Atrial Natriuretic Factor; D051792:Basic Helix-Loop-Helix Proteins; D004268:DNA-Binding Proteins; D050991:GATA4 Transcription Factor; D008156:Luciferases; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D051057:Proto-Oncogene Proteins c-akt; D012333:RNA, Messenger; D011993:Recombinant Fusion Proteins; D012097:Repressor Proteins; D014157:Transcription Factors; C497364:HEYL protein, human; C405694:Hairy, HRT1 protein; C485778:Hey2 protein, mouse; C494918:AKT1 protein, human; C494920:Akt1 protein, rat