1: Development. 2004 Oct;131(19):4709-23. Epub 2004 Aug 25. 

SMAD-mediated modulation of YY1 activity regulates the BMP response and
cardiac-specific expression of a GATA4/5/6-dependent chick Nkx2.5 enhancer.

Lee KH, Evans S, Ruan TY, Lassar AB.

Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical
School, 240 Longwood Avenue Boston, MA 02115, USA.

Prior work has indicated that BMP signals act in concert with FGF8, WNT11 and
WNT antagonists to induce the formation of cardiac tissue in the vertebrate
embryo. In an effort to understand how these signaling pathways control the
expression of key cardiac regulators, we have characterized the cis-regulatory
elements of the chick tinman homolog chick Nkx2.5. We find that at least three
distinct cardiac activating regions (CARs) of chick Nkx2.5 cooperate to regulate
early expression in the cardiac crescent and later segmental expression in the
developing heart. In this report, we focus our attention on a 3' BMP-responsive
enhancer, termed CAR3, which directs robust cardiac transgene expression. By
systematic mutagenesis and gel shift analysis of this enhancer, we demonstrate
that GATA4/5/6, YY1 and SMAD1/4 are all necessary for BMP-mediated induction and
heart-specific expression of CAR3. Adjacent YY1 and SMAD-binding sites within
CAR3 constitute a minimal BMP response element, and interaction of SMAD1/4 with
the N terminus of YY1 is required for BMP-mediated induction of CAR3. Our data
suggest that BMP-mediated activation of this regulatory region reflects both the
induction of GATA genes by BMP signals, as well as modulation of the
transcriptional activity of YY1 by direct interaction of this transcription
factor with BMP-activated SMADs.

PMID: 15329343 [PubMed - indexed for MEDLINE]


---------------------------------------------------------------