Tox: a multifunctional transcription factor and novel regulator of mammalian corticogenesis

Abstract

Major efforts are invested to characterize the factors controlling the proliferation of neural stem cells. During mammalian corticogenesis, our group has identified a small pool of genes that are transiently downregulated in the switch of neural stem cells to neurogenic division and reinduced in newborn neurons. Among these switch genes, we found Tox, a transcription factor with hitherto uncharacterized roles in the nervous system. Here, we investigated the role of Tox in corticogenesis by characterizing its expression at the tissue, cellular and temporal level. We found that Tox is regulated by calcineurin/Nfat signalling. Moreover, we combined DNA adenine methyltransferase identification (DamID) with deep sequencing to characterize the chromatin binding properties of Tox including its motif and downstream transcriptional targets including Sox2, Tbr2, Prox1 and other key factors. Finally, we manipulated Tox in the developing brain and validated its multiple roles in promoting neural stem cell proliferation and neurite outgrowth of newborn neurons. Our data provide a valuable resource to study the role of Tox in other tissues and highlight a novel key player in brain development.

Transcriptional Architecture of Synaptic Communication Delineates GABAergic Neuron Identity

“…Almost all well-studied TFs in embryonic precursors maintain expression within the same clade of mature PCPs (Figure 7D, E): whereas Lhx6, Sox6, Mafb, Satb1 are expressed in PV and SST populations (the MGE clade), Coup-TF2, Sp8, Prox1, Npas1, Npas3; are expressed in VIP populations (the CGE clade). We further discovered additional TFs with similar patterns: whereas Tox family members (Tox, Tox2, Tox3) (Artegiani et al, 2015) are restricted to the MGE clade, Nfi family members (Nfia’, Nfib’, Nfix) (Piper et al), Sall1 and Trp53i11 are restricted to the CGE clade. Importantly, by “reverse tracking” of their developmental history through screening the Allen Developmental Mouse Brain Atlas, we found that each of these TFs is indeed expressed in the embryonic MGE or CGE, consistent with their clade relationship (Figure 7I, Figure S7C).…”

DamID-seq: Genome-wide Mapping of Protein-DNA Interactions by High Throughput Sequencing of Adenine-methylated DNA Fragments

“…The latter is particularly helpful when the target protein is loosely or indirectly associated with DNA. DamID has been successfully used to map the binding sites of a variety of proteins including nuclear envelope proteins [4][5][6][7][8][9][10] , chromatin associated proteins [11][12][13] , chromatin modifying enzymes 14 , transcription factors and co-factors [15][16][17][18] and RNAi machineries 19 . The method is applicable in multiple organisms including S. cerevisiae 13 , S. pombe 7 , C. elegans 9,17 , D. melanogaster 5,11,18,20 , A. thaliana 21,22 as well as mouse and human cell lines 6,8,10,23,24 .…”

A molecular conundrum involving hypothalamic responses to and roles of long non-coding RNAs following food deprivation

“…Tox, otherwise known as the thymocyte selection-associated high mobility group box factor is an evolutionarily conserved DNA-binding protein which regulates transcription by modifying local chromatin structure and modulating the formation of multi-protein complexes 89 . There is no indication at this time that it is regulated by lncRNAs, but a recent publication has implicated Tox expression in neural stem cell commitment 90 . Finally, AK082527 lncRNA is expressed in an anti-sense direction relative to the Icam5 gene, which is very suggestive of a cis-regulatory role for this lncRNA in Icam5 expression.…”