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Jingchen Chen, Fangping Dai, Ajeesh Balakrishnan-Renuka, Florian Leese, Werner Schempp, Felix Schaller, Michael Marcus Hoffmann, Gabriela Morosan-Puopolo, Faisal Yusuf, Izak Johannes Bisschoff, Verena Chankiewitz, Jinglun Xue, Jingzhong Chen, Kang Ying, Beate Brand-Saberi

• \(\it ATOH8\) 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 \(\it ATOH8\) orthologues from 18 vertebrate species and 24 invertebrate species. The reconstruction of \(\it ATOH8\) 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 \(\it ATOH8\). 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 \(\it ATOH8\) which could drive the expression of EGFP reporter in the chicken embryo. In the opossum, both the coding region and regulatory elements of \(\it ATOH8\) 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, \(\it ATOH8\) was hosted in one chromosome which is a fusion product of two orthologous chromosomes in non-human primates. This unique chromosomal environment of human \(\it ATOH8\) probably subjects its expression to the regulation at chromosomal level. We deduce that the great interspecific differences found in both \(\it ATOH8\) gene sequence and its regulatory elements might be significant for the fine regulation of its spatiotemporal expression and roles of \(\it ATOH8\), thus orchestrating its function in different tissues and organisms.