Abstract
The transcriptional repressor REST regulates many neuronal genes by binding RE1 motifs. About one third of human RE1s are recently evolved and specific to primates. As changes in the activity of a transcription factor reverberate on its downstream targets, we assessed whether REST displays fast evolutionary rates in primates. We show that REST was targeted by very strong positive selection during primate evolution. Positive selection was also evident in the human lineage, with six selected sites located in a region that surrounds a VNTR in exon 4. Analysis of expression data indicated that REST brain expression peaks during aging in humans but not in other primates. Because a REST coding variant (rs3796529) was previously associated with protection from hippocampal atrophy in elderly subjects with mild cognitive impairment (MCI), we analyzed a cohort of Alzheimer disease (AD) continuum patients. Genotyping of two coding variants (rs3796529 and rs2227902) located in the region surrounding the VNTR indicated a role for rs2227902 in modulation of hippocampal volume loss, indirectly confirming a role for REST in neuroprotection. Experimental studies will be instrumental to determine the functional effect of positively selected sites in REST and the role of REST variants in neuropreservation/neurodegeneration.
Highlights
The Repressor Element 1 Silencing Transcription factor (REST, known as neuron restrictive silencer factor, NRSF) is a transcriptional regulator that binds a specific 21 bp motif (Repressor Element 1–RE1) in the regulatory regions of target genes[1, 2]
In elderly subjects with mild cognitive impairment (MCI), a disorder that has been associated with risk for dementia, a missense REST variant was associated with baseline hippocampal volume and with the rate of hippocampal grey matter (GM) density loss, suggesting that the minor allele of rs3796529 confers a
We report that a REST haplotype comprising a variant in linkage disequilibrium with the variable number tandem repeat (VNTR) modulates right hippocampal volume in an Italian cohort of Alzheimer’s Disease (AD) subjects
Summary
The Repressor Element 1 Silencing Transcription factor (REST, known as neuron restrictive silencer factor, NRSF) is a transcriptional regulator that binds a specific 21 bp motif (Repressor Element 1–RE1) in the regulatory regions of target genes[1, 2]. REST expression correlates with the up-regulation of protective stress response genes, as well as with the repression of genes that promote cell death These findings support the notion that REST is necessary during aging to maintain neuronal viability and to preserve cognitive functions[8]. REST and its target genes have been implicated in the pathogenesis of a number of different neurodegenerative diseases, including Alzheimer’s Disease (AD) clinical continuum, frontotemporal dementia, and dementia with Lewy bodies[8, 9] In these pathologies, REST is depleted in the nucleus of PFC and hippocampal neurons and colocalizes in autophagosomes together with pathological misfolded proteins (e.g. Aβ, phosphorilated Tau, TDP-43, α-synuclein). In elderly subjects with mild cognitive impairment (MCI), a disorder that has been associated with risk for dementia, a missense REST variant (rs3796529) was associated with baseline hippocampal volume and with the rate of hippocampal grey matter (GM) density loss, suggesting that the minor allele of rs3796529 confers a www.nature.com/scientificreports/
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
