Regulation of human MAPT gene expression

Caillet-Boudin et al. Molecular Neurodegeneration (2015) 10:28 DOI 10.1186/s13024-015-0025-8 REVIEW Open Access Regulation of human MAPT gene expression Marie-Laure Caillet-Boudin*, Luc Buée, Nicolas Sergeant and Bruno Lefebvre 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. Keywords: Tau, Tauopathy, MAPT, Alzheimer’s disease, Repeat sequences, CpG islands, Tau haplotype, Tau promoter, Tau splicing Introduction Tau proteins are expressed primarily in the brain and, more precisely, in neurons. These proteins were discovered in 1975 and identified as important mediators of cerebral microtubule polymerization and stabilization [1] (reviewed in [2, 3]). Since then, other roles for Tau proteins have been demonstrated. Tau is involved in axonal transport (reviewed in [4, 5]), synaptic plasticity/function (reviewed in [6, 7]) and nucleic acid protection [8, 9], depending on its cellular localization (cell body/axon, cytoplasmic membrane, or nucleus). The functional importance of Tau is underscored by the involvement of Tau deregulation in neurodegenerative diseases. Aggregation of hyperphosphorylated Tau proteins in degenerating neurons, which leads to the formation of neurofibrillary tangles, occurs in a group of pathologies termed tauopathies (reviewed in [3]). The relationship between Tau proteins and pathophysiology is supported by the identification of autosomal dominant mutations in the Tau gene, MAPT, in various tauopathies, such as frontotemporal dementia with parkinsonism linked to chromosome 17 (FTDP-17) (reviewed in [10, 11]). Although certain tauopathies are clearly pure neurodegenerative diseases, such as Alzheimer’s disease * Correspondence: Univ. Lille, UMR-S 1172, Inserm, CHU, 59000 Lille, France (AD), progressive supranuclear palsy (PSP), corticobasal degeneration (CBD), and FTDP-17, some are associated with the development of other pathologies, such as arteriovenous malformation [12], brain tumors (such as ganglion cell tumors) [13, 14], viral infection (such as subacute sclerosing panencephalitis (SSPE) [15] and postencephalitic parkinsonism [16]), developmental abnormalities (verrucose dysplasia [17]), Down syndrome [18], myotonic dystrophy (DM) [19], parkinsonism-dementia of Guam [16, 20], traumatic brain injury [21, 22], and Huntington’s disease [23]. Tau isoforms are translated from alternatively spliced mRNA, and some or all of these isoforms aggregate, depending on the pathology (reviewed in [3]). Deregulated Tau expression and missplicing have been reported in several pathologies. The direct involvement of a splicing defect has been clearly demonstrated for FTDP-17 and DM types 1 and 2 (reviewed in [24]). Some patients with amyotrophic lateral sclerosis (ALS) or frontotemporal lobar dementia (FTLD) exhibit the nearly complete absence of Tau protein in the cortex despite normal Tau mRNA expression. These latter two pathologies, ALS and FTLD, are characterized by the presence of ubiquitin-positive aggregates composed of TDP-43 (transactive response DNA binding protein 43 kDa) [25–27], as reviewed in [28]. Furthermore, MAPT is a major candidate involved in the mechanism of 17q21.31 microdeletion syndrome, a © 2015 Caillet-Boudin et al. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. The Creative Commons Public Domain Dedication waiver (http:// creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Caillet-Boudin et al. Molecular Neurodegeneration (2015) 10:28 pathology characterized by the microdeletion of a small chromosomal region (from 650 to 1,608 kb) containing several genes, including MAPT. The symptoms of 17q21.31 microdeletion syndrome include mental retardation, hypotonia and characteristic facial features. Pathological phenotypes have also been associated with microduplications or microtriplications containing MAPT [29–32]. One of the single-nucleotide polymorphisms (SNPs) within the MAPT locus has been found to be associated with AD in patients without ApoE e4 [33]. The MAPT locus is an important genetic risk factor for Parkinson’s disease (PD) [33–35]. Taken together, these data demonstrate the complexity of Tau expression in the brains of healthy individuals and patients with the above-mentioned diseases. More recently, several reports have suggested that Tau interferes with certain pathologies involving tissues other than the brain. For example, Tau aggregation has been reported in the muscles of patients suffering from inclusion body myositis (IBM), an inflammatory muscle disease [36, 37]. Furthermore, Tau expression may have a prognostic or predictive value in some cancers affecting various tissues, such as breast [38, 39], prostate [40, 41], ovary [42, 43], bladder [44], and stomach cancers [45]. Tau expression could be related to certain sub-types of cancer; for example, it is increased in hormonedependent breast cancer [39, 46]. Such an increase in Tau expression may result in resistance to microtubuletargeting drugs [43, 47–56]. Despite the importance of the deregulation of Tau expression/metabolism in many pathologies, the regulation of the expression of the MAPT gene, which encodes Tau protein, has been the subject of few articles; more articles have focused on the function of Tau protein or its roles in various pathologies. The most commonly studied aspects include MAPT haplotypes and Tau RNA splicing because of their involvement in certain tauopathies (for examples, see reviews [57–61]). Research regarding the epigenetic regulation of Tau expression is increasing. However, some aspects of Tau gene expression, such as the possible existence of different promoters and the potential role of the repeated motifs fou (...truncated)