Structural and functional characterization of H2 haplotype MAPT promoter: unique neurospecific domains and a hypoxia-inducible element would enhance rationally targeted tauopathy research for Alzheimer's disease

dc.contributor.authorMaloney, Bryan
dc.contributor.authorLahiri, Debomoy K.
dc.contributor.departmentPsychiatry, School of Medicine
dc.date.accessioned2025-07-10T16:25:22Z
dc.date.available2025-07-10T16:25:22Z
dc.date.issued2012
dc.description.abstractAlzheimer's disease (AD) is the leading cause of dementia in the elderly. Extraneuronal plaque comprising mostly the amyloid β peptide and intraneuronal tangles of hyperphosphorylated microtubule-associated τ protein (τ, gene MAPT) are typical of AD. Misfolded τ is also implicated in Parkinson's disease and frontotemporal dementia. We aim to understand the regulation of the human MAPT promoter by mapping its functional domains. We subcloned a 4868 base pair (bp) fragment from human BAC RPCI-11 100C5. Sequence analysis revealed an H2 haplotype MAPT promoter, 5'-UTR, and intronal fragment. Database analysis of the fragment showed 50%-75% homology with mouse and >90% with rhesus monkey. Comparison with human H1 sequences revealed differences that crossed predicted transcription factor sites. DNA-protein interaction studies by electrophoretic mobility shift assay suggested hypoxia response and an active specificity protein 1 (SP1) site in the 5'-untranslated region. Transfection of a series of MAPT promoter deletions revealed unique functional domains. The distal-most had different activities in neuronal vs. non-neuronal cells. We have cloned, sequenced, and functionally characterized a 4868bp fragment of the human MAPT 5'-flanking region, including the core promoter region (-302/+4), neurospecific domains (-4364/-1992 and +293/+504, relative to +1 TSS), and a hypoxia-inducible element (+60/+84). Our work extended functional analysis of the MAPT sequence further upstream, and explores cell-type specificity of MAPT promoter activity. Finally, we provided direct comparison of likely transcription factor binding sites, which are useful to understand differences between H1/H2 pathogenic associations.
dc.eprint.versionAuthor's manuscript
dc.identifier.citationMaloney B, Lahiri DK. Structural and functional characterization of H2 haplotype MAPT promoter: unique neurospecific domains and a hypoxia-inducible element would enhance rationally targeted tauopathy research for Alzheimer's disease. Gene. 2012;501(1):63-78. doi:10.1016/j.gene.2012.01.049
dc.identifier.urihttps://hdl.handle.net/1805/49346
dc.language.isoen_US
dc.publisherElsevier
dc.relation.isversionof10.1016/j.gene.2012.01.049
dc.relation.journalGene
dc.rightsPublisher Policy
dc.sourcePMC
dc.subjectCell type specificity
dc.subjectGene regulation
dc.subjectH2 haplotype
dc.subjectNeurofibrillary tangles
dc.subjectPromoter
dc.subjectTau
dc.titleStructural and functional characterization of H2 haplotype MAPT promoter: unique neurospecific domains and a hypoxia-inducible element would enhance rationally targeted tauopathy research for Alzheimer's disease
dc.typeArticle
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