Human homologue of maid: A dominant inhibitory helix-loop-helix protein associated with liver-specific gene expression

The helix-loop-helix (HLH) family of transcriptional. regulatory proteins a re key regulators in numerous developmental processes. The class I HLH prot eins, such as E12 are ubiquitously expressed. Class II HLH proteins, such a s MyoD, are expressed in a tissue-specific manner, Class I and II heterodim ers can bind to E-boxes (CANNTG) and regulate lineage commitments of embryo nic cells. In an attempt to identify partners for the E12 protein that may exert control during liver development, we performed the yeast 2-hybrid scr een using an expression complementary DNA library from human fetal liver. A novel dominant inhibitory HLH factor, designated HHM (human homologue of m aid), was isolated and characterized. HHM is structurally related to the Id family and was highly expressed in brain, pituitary gland, lung, heart, pl acenta, fetal liver, and bone marrow. HHM physically interacted with E12 in vitro and in mammalian cells. Comparison of the dominant inhibitory effect s of HHM and Id2 on the binding of E12/MyoD dimer to an E-box element revea led a weaker inhibition by HHM. However, HHM but not Id2 specifically inhib ited the luciferase gene activation induced by hepatic nuclear factor 4 (HN F4) promoter. The HHM was transiently expressed during stem-cell-driven reg eneration of the liver at the stage in which the early basophilic foci of h epatocytes started to appear. These results suggest that HHM is a novel typ e of dominant inhibitory HLH protein that might modulate liver-specific gen e expression.