Many bHLH proteins are involved in cardiac development and cardiovascular diseases. Herein, we identified and characterized the human homologue (hnulp1) of mouse gene nulp1. The predicted protein contains a bHLH domain and a DUF654 domain in N-terminal and C-terminal, respectively. Northern blot analysis shows that a 2.3-kb transcript expressed broadly in early human embryonic and adult tissues, especially with a higher level in adult heart. hnulp1 is a transcription repressor when fused to GAL4 DNA-binding domain and co-transfected with VP-16, in which DUF654 motif represents the basal transcriptional repressive activity. Treatment of cells with trichostatin A can relieve this repression, suggesting that the DUF654 motif acts through increasing deacetylase activity at the GAL4-driven promoter. Overexpression of hnulp1 protein in COS-7 cells inhibits the transcriptional activity of serum response factor (SRF), suggesting that hnulp1 may act as a novel bHLH transcriptional repressor in SRF signaling pathway to mediate cellular functions. (c) 2006 Elsevier Inc. All rights reserved.