Figure 1.

TDP-43-mediated transcriptional regulation. Genes for which TDP-43 has been shown to regulate the transcription by acting at the promoter level are illustrated in their context. (a–e) Transcriptional repression, involving the direct binding of TDP-43 to the target DNA regulatory region. (a) TDP-43 binding on Acrv1 promoter via two GTGTGT-motifs controls the production of Sp-10 protein during mouse spermatogenesis. TDP-43 at Acrv1 promoter is still observed when histones acquire activating modifications (H3K9Ac, H3K4me3, increases in RNA-pol II) and transcription starts in spermatids. In the liver, TDP-43 binding and inactive chromatin mark H3K9me2 associates with Acrv1 inhibition (adapted from [40]). (b) Repressive potential of TDP-43 on the c-fos promoter. Tethering of TDP-43 to a reporter plasmid using Gal4 DNA Binding Domain (DBD), fused to TDP-43 at Gal4 binding sequences (blue boxes), upstream of the c-fos promoter, represses the promoter-induced luciferase expression (adapted from [40]). (c) In neurons, TDP-43 represses the promoter of VSP4B, ensuring recycling endosome transport. The repression occurs via the binding of TDP-43 at a GT-rich region less than 1 kb before VPS4B TSS. Loss of TDP-43 derepresses the VPS4B promoter, leading to loss of dendrites and dendritic spines (adapted from [41]). (d) TDP-43 contributes to the supplementary X inactivation (Xi) and X-linked genes in females. TDP-43 interacts with Xist RNA in female cells together with other Xist RNA binding proteins: PTBP1, MATR3, or CELF1. The TDP-43 strongest binding within Xist occurs at the 3′ end of the E-repeat containing multiple (GU)n tracts and persists after completion of X inactivation. Depletion of TDP-43 induces significant nuclear dispersal of Xist and defects in DNA compaction (adapted from [44]). (e) TDP-43 binds to a short 40 bp region located from −200 to −160 of Cyp8b1 promoter in liver and represses its expression. The decrease in Cyp8b1 results in the activation of FXR and an increase in apoC2 levels and diffusion, resulting in enhanced triglyceride (TG) clearance in several mice tissues (muscle, heart, and adipose cells). lncLSTR, a liver-specific lncRNA, binds TDP-43 protein and impedes its binding onto Cyp8b1 promoter, consequently counteracting TG clearance (adapted from [45]). (f–h) Transcriptional activation. (f) TDP-43 binds to and activates the TNF-alpha promoter at an LPS-sensitive binding site, located −550 to −487, and mediates the activation of Thd1 macrophage-like. siRNA against TDP-43 reduces the LPS induction of TNF-alpha by 50% (adapted from [46]). (g) TDP-43 is a direct transcriptional activator of the CHOP/GADD153 promoter in SH-SY5Y, provoking cell death. Binding within the CHOP promoter potentially occurs in a region comprised within the bp −300 and −30 from the TSS. TDP-43 also increases CHOP mRNA stability. Acetylation of TDP-43 at lysine 145 and 192 impedes TDP-43 activation of the CHOP promoter (adapted from [48]). (h) During C2C12 differentiation, TDP-43 is tethered by the muscle-enriched lncRNA Myolinc to the promoter of several genes linked to the differentiation of myoblasts into myocytes, such as Acta1, MyoD1, Filip1, and others (adapted from [42]). (i) Circplot-like summary of the different modalities by which TDP-43 regulates gene expression. TDP-43 can act at “single” or “multiple” targets “functionally” (e.g., the myogenesis pathway) or “spatially” (chromosome X) related. It can be “repressive” or “activating”, involving lncRNAs acting either by “evicting” TDP-43 or tethering it, thus acting as a “scaffold”. Generally, direct binding of TDP-43 on its target’s promoter has been demonstrated. The dependence for DNA binding on GT-rich sequences (“GT-rich”) or not (“Not GT”), when known, is shown, but is has not always been specified (“?”).