Diversification and Molecular Evolution of ATOH8, a Gene Encoding a bHLH Transcription Factor

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.

The role of Hath6, a novel shear stress-responsive transcription factor, in endothelial differentiation and function modulation

“…In general, animal models rather than human subjects are used in development and gene-function studies owing to ethical issues. However, the species variation of ATOH8 might indicate that it has different functions in different cellular contexts, especially for Hath6, as previously suggested (Chen et al, 2011). The findings from hESC and EC studies emphasized the significance of Hath6 in the control of endothelial-specific gene expression, cell-fate determination and possibly the genetic program that permits mechanotransduction.…”

Identification and validation of an eight‐gene expression signature for predicting high Fuhrman grade renal cell carcinoma

“…To some extent, this result demonstrated that the signature could explain the nature of the Fuhrman grading system based upon nuclear size, and the shape and prominence of nucleoli . ATOH8 is recognized as a transcriptional factor that has important roles in cell differentiation and developmental biology . ATP1A3 and CNGA1 are important in cellular energy metabolism, while CHMP4C belongs to the chromatin‐modifying protein family and is associated with nucleus organization .…”

Evolving gene regulatory networks into cellular networks guiding adaptive behavior: an outline how single cells could have evolved into a centralized neurosensory system

“…For example only four bHLH genes and their orthologs (Ascl1, Atoh1/7, Neurog1/2 and Neurod1) are necessary for the development of ∼90% of the neurons in the mammalian brain [cerebellum, cochlear nuclei, large areas of the cortex and sensory cells and neurons of the eye and ear (Bermingham, et al, 2001, Pan, et al, 2009)] and all sensory neurons bringing information into the brain. Indeed, most of the group A bHLH genes are associated with neurosensory development (Chen, et al, 2011, Imayoshi and Kageyama, 2014) and seem to be linked to the evolution of neurons (Fig. 2).…”