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. 2023 Sep 7;24(18):13807. doi: 10.3390/ijms241813807

Figure 7.

Figure 7

TARDBP locus promoter regulation. The main TSS identified for TARDBP and TDP-43 FL is from Seq NM_007375.4 (TSS1), starting at chr1; 11072711(+strand) (GRCh37/hg19). It is located in exon1 (Ex1), 102bp before intron1. Other confirmed (solid arrows, TSS2) or predicted (dashed arrows) TSSs lay upstream or downstream of TSS1 and are displayed. A minor TSS (TSS2) within exon2 (Ex2) has been identified in human fetal brain, without a precise localisation reported. Note that since the predicted TSSs at −32 served as a reference for start-numbering in different works, it is indicated here as ≪+1*≫, representing a shift of −32 bp relative to TDP−43 FL Seq transcript NM_007375.4 TSS (TSS1). The TARDBP promoter region is bipartite, with two core promoters (dark green boxes): one proximal TATA-less promoter located before the exon1 (−327–+1) and within (−451–−230); and one distal located at +972_+1094, i.e., within the intron1 position +850_+972. The proximal TATA-less promoter is necessary for the minimal promoter activity in all tested cell lines. Other regulatory features identified are positive (green boxes) and negative (red boxes) regulatory regions. A 58 bp region (−281–−223) in the proximal core is crucial for promoter activity. The upstream regulatory region (−927–−300), holding an iMotif (−371–−309), is important for maximal activity. Sequences in the +1–+123 region, encompassing exon1, positively enhance transcription. In the distal intron1 promoter, the region +788–+972 (+666–+850 of intron 1) is repressive. Epigenetic characteristics of TARDBP locus in the human cortex are displayed, as in Figure 5. H3K4me3 histone modification (green bars), the enrichment of which marks the active promoter regions and is found upstream of exon 1 (TSS) down to exon 2. The promoter region extending from −836 to + 1106 contains 125 CpG mostly within 3 CpG islands (CGI, dashed blue boxes) (−874 to + 1069). In the human cortex, along the promoter region, the CpG score (red bars) shows different degrees of CpG methylation. The region from CGI 2–3 down to exon 2 is not methylated. TF action and binding zone: factors shown to activate or repress TARDBP promoter are displayed on top of the locus by green or red zone, respectively. LPS and neuronal hyperactivity (triggered, e.g., by TEA, inhibited by TTX) positively regulate the TARDBP promoter, although the specific regions have not been defined yet. TDP-43 itself can repress its cognate promoter and, in particular, through the proximal upstream promoter. TDP-43mut: two TDP-43 mutants (G348C, A382T) activate the intron1 distal promoter. HNRNP-K binds to the iMotif in the upstream tropism. ALS-linked variants: position of variants identified in ALS patients, with their non-different higher frequency (f(ALS)) relative to frequency in HapMap controls (f(controls)), or found in ALS only, are depicted in white-to-purple circles within the TARDBP regulatory region. A (c.1-562t>c, rs9430335); B (c.1-100t>c; rs968545); C (c.13g>a); D (c.122+85c>t); E (c.122+95c>t); F (c.122+150delg); G (c.122+218c>t); H (c.122+284g>t); I (c.123-450a>c); J (c.123-262-263del); K (c.170c>t (p.N12N)); L (c.198t>c (p.A66A)) (see [175]). None of these variants were found to have a significant incidence on the TARDBP promoter in the tested conditions, and no OMIM variant is described in this region to date. All tracks are from UCSC Genome Browser on the human (GRCh37/hg19).