Regulation of human MAPT gene expression

Abstract

The number of known pathologies involving deregulated Tau expression/metabolism is increasing. Indeed, in addition to tauopathies, which comprise approximately 30 diseases characterized by neuronal aggregation of hyperphosphorylated Tau in brain neurons, this protein has also been associated with various other pathologies such as cancer, inclusion body myositis, and microdeletion/microduplication syndromes, suggesting its possible function in peripheral tissues. In addition to Tau aggregation, Tau deregulation can occur at the expression and/or splicing levels, as has been clearly demonstrated in some of these pathologies. Here, we aim to review current knowledge regarding the regulation of human MAPT gene expression at the DNA and RNA levels to provide a better understanding of its possible deregulation. Several aspects, including repeated motifs, CpG island/methylation, and haplotypes at the DNA level, as well as the key regions involved in mRNA expression and stability and the splicing patterns of different mRNA isoforms at the RNA level, will be discussed.

Fig. 1

DNA satellite sequences and CpG islands in the MAPT gene. Only the repeats discussed in the text are indicated. The complete list can be found on the UCSC site. White, non-coding regions; color, coding regions; gray, constitutive coding exons. Yellow, orange, pink, green, purple and blue represent the alternative exons 2, 3, 4A, 6, 8 and 10, respectively

Fig. 2

Organization of the rat, mouse and human Tau promoters. The lengths of the various regions of the promoter are not representative of their precise localizations but are dependent on the cloning technique. Thus, differences in the length of a determined region among species are not significant. Note the influence of allelic variants on promoter activity. CpG islands present in the promoter are indicated

Fig. 3

Transcription initiation sites (black perpendicular arrow) and termination sites (simple gray arrow). These sites enable the expression of the complete Tau transcript/protein. For other sites, see Fig. 4b. Red numbers: initiation sites according to the database. Green numbers: initiation sites described in [77]. FS: forward strand, RS: reverse strand

Fig. 4

Splicing patterns of human Tau transcripts. a Classical splicing pattern described in the literature. The insertion of exons 4A and 6 rarely occurs in the brain (shaded in pale orange) and varies according to which 3’ splice site is used. E8 insertion (shaded in dark orange) has not been reported in humans but has been described in different animal models and in the human Ensembl database. b Hypothetical splicing according to the Ensembl database. The MAPT numbers correspond to those in the Ensembl database. White, non-coding regions; gray, constitutive coding exons. Yellow, orange, pink, green, purple and blue represent the alternative exons 2, 3, 4A, 6, 8 and 10, respectively