Serum response factor, an enriched cardiac mesoderm obligatory factor, is a downstream gene target for Tbx genes. J Biol Chem 2005 Mar 25;280(12):11816-28
Date
12/14/2004Pubmed ID
15591049DOI
10.1074/jbc.M412408200Scopus ID
2-s2.0-20144374695 (requires institutional sign-in at Scopus site) 44 CitationsAbstract
We tested the idea that T-box factors direct serum response factor (SRF) gene activity early in development. Analysis of SRF-LacZ "knock-in" mice showed highly restricted expression in early embryonic cardiac and skeletal muscle mesoderm and neuroectoderm. Examination of the SRF gene for regulatory regions by linking the promoter and 5'-flanking sequences, up to 5.5 kb, failed to target LacZ transgene activity to the heart and the tail pre-somitic mesenchyme. However, linkage of a minimal SRF promoter with the SRF 3'-untranslated region (UTR), inundated with multimeric T-box binding sites (TBEs), restored robust reporter gene activity to embryonic heart and tail. Finer dissection of the 3'-UTR to a small cluster of TBEs also stimulated transgene activity in the cardiac forming region and the tail, however, when the TBEs contained within these DNA sequences were mutated, preventing Tbx binding, transgene activity was lost. Tbx2, Tbx5, and the cardiac-enriched MYST family histone acetyltransferase TIP60, were observed to be mutual interactive cofactors through the TIP60 zinc finger and the T-box of the Tbx factors. In SRF-null ES cells, TIP60, Tbx2, and Tbx5 were sufficient to stimulate co-transfected SRF reporter activity, however this activity required the presence of the SRF 3'-UTR. SRF gene transactivation was blocked by two distinct TIP60 mutants, in which either the histone acetyltransferase domain was inactivated or the Zn finger-protein binding domain was excised. Our study supports the idea that SRF embryonic cardiac gene expression is dependent upon the SRF 3'-UTR enhancer, Tbx2, Tbx5, and TIP60 histone acetyltransferase activity.
Author List
Barron MR, Belaguli NS, Zhang SX, Trinh M, Iyer D, Merlo X, Lough JW, Parmacek MS, Bruneau BG, Schwartz RJAuthors
Matthew R. Barron PhD Research Scientist I in the Surgery department at Medical College of WisconsinJohn W. Lough PhD Professor in the Cell Biology, Neurobiology and Anatomy department at Medical College of Wisconsin
MESH terms used to index this publication - Major topics in bold
3' Untranslated Regions5' Flanking Region
Acetyltransferases
Animals
Base Sequence
Enhancer Elements, Genetic
Gene Expression Regulation, Developmental
Heart
Histone Acetyltransferases
Mesoderm
Mice
Molecular Sequence Data
Muscle, Skeletal
Promoter Regions, Genetic
Serum Response Factor
T-Box Domain Proteins
Transcriptional Activation