Abstract
ATOH8 is a bHLH domain transcription factor implicated in the development of the nervous system, kidney, pancreas, retina and muscle. In the present study, we collected sequence of ATOH8 orthologues from 18 vertebrate species and 24 invertebrate species. The reconstruction of ATOH8 phylogeny and sequence analysis showed that this gene underwent notable divergences during evolution. For those vertebrate species investigated, we analyzed the gene structure and regulatory elements of ATOH8. We found that the bHLH domain of vertebrate ATOH8 was highly conserved. Mammals retained some specific amino acids in contrast to the non-mammalian orthologues. Mammals also developed another potential isoform, verified by a human expressed sequence tag (EST). Comparative genomic analyses of the regulatory elements revealed a replacement of the ancestral TATA box by CpG-islands in the eutherian mammals and an evolutionary tendency for TATA box reduction in vertebrates in general. We furthermore identified the region of the effective promoter of human ATOH8 which could drive the expression of EGFP reporter in the chicken embryo. In the opossum, both the coding region and regulatory elements of ATOH8 have some special features, such as the unique extended C-terminus encoded by the third exon and absence of both CpG islands and TATA elements in the regulatory region. Our gene mapping data showed that in human, ATOH8 was hosted in one chromosome which is a fusion product of two orthologous chromosomes in non-human primates. This unique chromosomal environment of human ATOH8 probably subjects its expression to the regulation at chromosomal level. We deduce that the great interspecific differences found in both ATOH8 gene sequence and its regulatory elements might be significant for the fine regulation of its spatiotemporal expression and roles of ATOH8, thus orchestrating its function in different tissues and organisms.
Highlights
BHLH transcription factors play very important regulatory roles during embryonic development, e.g. in neurogenesis, myogenesis, hematopoiesis, sex determination, and gut development [1]
Our analysis showed that four exons which we termed as exon1, exon2, exon3a and exon3b were present within ATOH8 gene locus of eutherian mammals
Exon3a was verified by an expressed sequence tag (EST) (AL831857.1) from the amygdala of the human brain, which with exon1 and exon2 may form another isoform of ATOH8
Summary
BHLH transcription factors play very important regulatory roles during embryonic development, e.g. in neurogenesis, myogenesis, hematopoiesis, sex determination, and gut development [1]. ATOH8 belongs to group A of bHLH transcription factors [1]. It is classified as a member of NET family within the atonal superfamily which includes families of NeuroD, Neurogenin, Atonal, Oligo, Beta, Delilah, Mist and NET [2,3]. An altered ATOH8 expression level is reported in glioblastoma multiforme [12]. Considering these multiple implications of ATOH8 in different biological, developmental and pathological processes, we were intrigued to know if the function and regulation of expression of ATOH8 are conserved across different evolutionary lineages
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