Genomic and cellular context-dependent expression of the human ELMO1 gene transcript variants

Engulfment and cell motility protein 1 (Elmo1) forms a complex with Dedicator of cytokinesis (Dock) 1-5 and promotes GTP-loading of Rac1, the major agent of cell movement. While the pathophysiological roles of Elmo1 have expanded from apoptotic cell engulfment to cancer, inflammation, diabetic nephropathy and cardiomyopathy, little information is available on its transcriptional regulation. Genome databases indicate at least five transcript variants for human ELMO1: the variants V1, V4 and V5 encode a full-length 727 aa protein, whereas V2 and V3 encode a truncated Elmo1 of 247 aa that lacks N-terminal domains. A CpG island promoter drives the major V1 transcript, while an LTR12 drives V5 in intron 1, one of the three LTR12 family of retroviral elements in ELMO1. In contrast, the short-forms V2 and V3 contain CAT-TATA type promoters. Examination of various cell lines by RT-qPCR designed to detect individual transcripts showed that basal transcriptions of the variants were very low to undetectable in cultured cells. However, treatments with Trichostatin A, a histone deacetylase inhibitor, or with 5-Aza-2'-deoxycytidine, a DNA methyl transferase inhibitor, significantly upregulated V1, V4, V5 and V2 expression in a cell line-specific manner, indicating that these transcripts are epigenetically regulated. Another LTR12D transposon in intron 13 also drives an unannotated transcript stimulated by these inhibitors. Finally, we found the levels of V2 transcripts in the mouse and human brain exceed those of V1, suggesting a brain-specific regulation and role of V2 protein.