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42 THE N-TERMINUS OF FOG-2 INTERACTS WITH METASTASIS-ASSOCIATED PROTEINS 1 AND 2 TO MEDIATE TRANSCRIPTIONAL REPRESSION DURING CARDIAC DEVELOPMENT.
  1. S. A. Samant,
  2. A. E. Roche,
  3. E. C. Svensson
  1. Department of Medicine, The University of Chicago, Chicago, IL

Abstract

Mutations in several transcription factors that regulate cardiac development have recently been described to cause congenital heart disease in humans. A greater understanding of the molecular mechanisms that regulate heart formation may help identify other genes that when mutated will result in human congenital heart disease. FOG-2 is one such gene that encodes a transcriptional corepressor expressed in the developing heart. It is critical for proper cardiac morphogenesis as mice deficient in this factor die during midgestation of cardiac malformations. We have previously shown that FOG-2 physically interacts with GATA4 and attenuates GATA4's ability to activate cardiac specific gene expression. This repression is mediated by a domain of FOG-2 localized to its N-terminus, termed the FOG repression motif. To gain further insights into the molecular mechanism responsible for this repression, we took a biochemical approach to identify factors that interact with FOG repression motif. Using MALDI-TOF mass spectrometry, we identified seven proteins from rat neonatal cardiac nuclear extracts that copurified with a FOG-2-GST fusion protein. All of these proteins have been previously described to be subunits of a nucleosome-remodeling complex called the NuRD complex. To determine which of the NuRD subunits directly interact with the FOG repression motif, we used a series of in vitro binding assays. We found that MTA-1 and MTA-2 specifically bound to the N-terminus of FOG-2 but not to a mutant form of the N-terminus that is unable to mediate repression. In situ hybridization revealed that both MTA-1 and MTA-2 are expressed in the developing heart during mouse embryogenesis. Taken together, these results suggest that FOG-2 mediates transcriptional repression during cardiac development by the recruitment of the NuRD complex to GATA-dependent promoters leading to the remodeling of the local chromatin structure and the attenuation of gene expression.

This work was supported by NIH HL071063 and a grant from the Schweppe Foundation.

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