The possible functions of duplicated ets (GGAA) motifs located near transcription start sites of various human genes

Abstract

Transcription is one of the most fundamental nuclear functions and is an enzyme complex-mediated reaction that converts DNA sequences into mRNA. Analyzing DNA sequences of 5'-flanking regions of several human genes that respond to 12-O-tetradecanoyl-phorbol-13-acetate (TPA) in HL-60 cells, we have identified that the ets (GGAA) motifs are duplicated, overlapped, or clustered within a 500-bp distance from the most 5'-upstream region of the cDNA. Multiple protein factors including Ets family proteins are known to recognize and bind to the GGAA containing sequences. In addition, it has been reported that the ets motifs play important roles in regulation of various promoters. Here, we propose a molecular mechanism, defined by the presence of duplication and multiplication of the GGAA motifs, that is responsible for the initiation of transcription of several genes and for the recruitment of binding proteins to the transcription start site (TSS) of TATA-less promoters.

Fig. 1

Most of the 5′-upstream regions having duplicated GGAA motifs are TATA-less. a The number of genes that have duplicated GGAA consensus 14-bp sequence [14] in the 2,000 bp upstream from TSS was 469. Among them, 372 genes have no TATA-box within 500 bp upstream. b The number of genes that have duplicated GGAA consensus 14-bp sequencein the 2,000 bp upstream and GGAA(TTCC) overlapping within 500 bp upstream of TSS was 345. Among them, 279 genes have no TATA-box within 500 bp upstream. Numbers of genes from the Ensemble database are shown

Fig. 2

Hypothetical transcription controlling system in which duplicated GGAA (TTCC) motifs and Ets family proteins are involved. Closed circles represent GGAA (TTCC) motifs that are located near the TSS. The transcription activity is indicated by the size of the arrows. Multiple Ets family proteins, which are indicated by open squares, closed squares, triangles, and diamonds, could be induced by differentiation-inducing signals, apoptosis-inducing signals or specific cytokines. Their redundant occupancy around the TSS can regulate variable gene expression with subtle changes, depending on the combinations of the binding proteins. The over-transcribed mRNAs may be further regulated or fine-tuned by micro RNAs