The basic helix-loop-helix (bHLH) transcription factors (TFs) are essential in development and disease. Their function is regulated at multiple levels, including the structuring of homo- or heterodimeric forms among members of the family. Because most bHLH TFs have numerous dimerization partners, the commonly used overexpression or deletion experimental approaches in humans often generate results influenced by the altered regulatory balance of the TF network. To study the direct transcriptional role of two human bHLH TFs, we expressed them in an isolated system (yeast) with no additional tissue-specific bHLH TFs. The transcriptional effect was measured utilizing a GFP reporter controlled by human regulatory sequences containing different amounts of the bHLH TF consensus binding sites, the E-boxes. The individual transcriptional contributions of heterodimeric SCX-E47 or homodimeric E47 were compared over two human regulatory regions implicated in fibrosis: COL1A2 and TGFB1. Briefly, the heterodimeric SCX-E47 was the best activating form. The COL1A2 regulatory region showed the most significant transcriptional changes despite having fewer E-boxes (five) than the TGFB1 region (13). Finally, the context of the nearby TF binding sites and the core promoter was also relevant for the final individual transcriptional effect of the bHLH TFs tested.