Abstract 1473: Identification Of A New NRSF-binding Partner, Zfp90, Which Negatively Regulates The Repression Activity Of NRSF, A Critical Transcriptional Regulator Of Cardiac Fetal Gene Program
Neuron-restrictive silencer factor, NRSF is a Zn-finger transcription factor that specifically binds to DNA sequence called NRSE to repress the transcription. NRSF is involved in various biological processes, such as neuronal differentiation, carcinogenesis, and cardiac homeostasis. We previously reported that NRSF regulates the transcription of multiple fetal cardiac genes. Cardiac-specific overexpression of a dominant-negative form of NRSF in mice induced reactivation of fetal cardiac gene program, cardiac dysfunction, and sudden arrhythmic death, suggesting NRSF plays important roles in normal cardiac homeostasis. However, the molecular mechanisms or signaling pathways that regulate the activity of NRSF have not been well understood. In an attempt to clarify the regulators of NRSF, we performed yeast two-hybrid screening using NRSF as bait and identified Zfp90 as NRSF-binding protein. NRSF and Zfp90 co-localize in the nuclear, and Zn-finger domain of NRSF specifically interacted with KRAB domain of Zfp90. To monitor the activity of NRSF sensitively, we made NRSF-responsive reporters using NRSE sequence of BNP promoter and established assay system for estimating the NRSF activity. In this assay system, expression of NRSF repressed the reporter activity and co-expression of Zfp90 restored it. Furthermore the expression levels of Zfp90 were elevated in the hearts with cardiomyopathy. These results suggest that Zfp90 functions as a negative regulator of NRSF and contributes to the genetic remodeling during the development of cardiomyopathy..