Comparative Genomics of Neuroglobin Reveals Its Early Origins

Abstract

BackgroundNeuroglobin (Ngb) is a hexacoordinated globin expressed mainly in the central and peripheral nervous system of vertebrates. Although several hypotheses have been put forward regarding the role of neuroglobin, its definite function remains uncertain. Ngb appears to have a neuro-protective role enhancing cell viability under hypoxia and other types of oxidative stress. Ngb is phylogenetically ancient and has a substitution rate nearly four times lower than that of other vertebrate globins, e.g. hemoglobin. Despite its high sequence conservation among vertebrates Ngb seems to be elusive in invertebrates.Principal FindingsWe determined candidate orthologs in invertebrates and identified a globin of the placozoan Trichoplax adhaerens that is most likely orthologous to vertebrate Ngb and confirmed the orthologous relationship of the polymeric globin of the sea urchin Strongylocentrotus purpuratus to Ngb. The putative orthologous globin genes are located next to genes orthologous to vertebrate POMT2 similarly to localization of vertebrate Ngb. The shared syntenic position of the globins from Trichoplax, the sea urchin and of vertebrate Ngb strongly suggests that they are orthologous. A search for conserved transcription factor binding sites (TFBSs) in the promoter regions of the Ngb genes of different vertebrates via phylogenetic footprinting revealed several TFBSs, which may contribute to the specific expression of Ngb, whereas a comparative analysis with myoglobin revealed several common TFBSs, suggestive of regulatory mechanisms common to globin genes.SignificanceIdentification of the placozoan and echinoderm genes orthologous to vertebrate neuroglobin strongly supports the hypothesis of the early evolutionary origin of this globin, as it shows that neuroglobin was already present in the placozoan-bilaterian last common ancestor. Computational determination of the transcription factor binding sites repertoire provides on the one hand a set of transcriptional factors that are responsible for the specific expression of the Ngb genes and on the other hand a set of factors potentially controlling expression of a couple of different globin genes.

Genomic lens on neuroglobin transcription

“…Predictive analysis of the consensus sequences that can be recognized by various TFs in NGB promoter was already reported and some TFs have been experimentally validated by chromatin immunoprecipitation, for example, NFkB and Sp1 . Figure shows the results we obtained using matrix‐scan algorithms (Jaspar CORE 2009, NHRScan) reported in top and bottom panels, respectively.…”

Overexpressed neuroglobin raises threshold for nitric oxide-induced impairment of mitochondrial respiratory activities and stress signaling in primary cortical neurons

“…Despite its early evolutionary origins and strong sequence and structure conservation [2], its precise function is not well understood [3]. Neuroglobin (Ngb) has been implicated in several paradigms of neuroprotection, involving improved oxygen homeostasis, oxygen sensing, neutralization of free radicals, redox cycling [4, 5, 6, 7, 8, 9], as well as neuron type-specific regulatory functions [10, 11].…”

Globins in the marine Annelid Platynereis dumerilii shed new light on hemoglobin evolution in Bilaterians

“…Many phylogenetic studies have focused on the hemoglobins of Mammals and Vertebrates in general, starting with the seminal work of Zuckerkandl and Pauling (1962). A smaller number of studies have focused on the evolution of Metazoan globins (4)(5)(6)(7). These studies have shown that Vertebrate hemoglobins and the related myoglobins are only a small branch in a vast tree of animal globins, some of which are used for respiratory functions but many others have still unknown functions.…”