Abstract for presentation at 11th International Congress of Human Genetics

Overdose of a short HSA21 segment causes reduction of REST transcript levels in humans and mouse Down syndrome models

  • Dr Claire Mulligan, Barts & The London, Queen Mary College Medical School, United Kingdom
  • Dr Samuel Deutsch, University of Geneva Medical School, Switzerland
  • Dr Gareth Denyer, University of Sydney, Australia
  • Prof Charles Epstein, University of California, San Francisco, United States
  • Prof Elizabeth Fisher, Prion Unit, UCL, United Kingdom
  • Prof Victor Tybulewicz, NIMR, MRC, Mill Hill, United Kingdom
  • Prof Stylianos Antonarakis, University of Geneva Medical School, Switzerland
  • Prof Dean Nizetic, Barts & The London, Queen Mary College Medical School, United Kingdom

    • Down syndrome (DS), caused by trisomy of human chromosome 21 (HSA21), is the most common human genetic birth defect and cause of mental retardation, displaying neural phenotypes shared by DS individuals and mouse models. However, the molecular pathogenetic mechanisms reproducible in both systems have yet to be identified. We compared mouse ES cells carrying an extra copy of HSA21 with their wild-type counterparts using Affymetrix microarrays. Unsupervised hierarchical clustering successfully segregated the two cell lines, indicating a global effect of trisomy 21 on the undifferentiated ES cell transcriptome. RT-PCR confirmation verified that the neuron-restrictive silencer factor REST, a key regulator of neural differentiation, and its downstream target Scg10 were significantly decreased intrisomic cells. Identical changes were also detected in RNA from brains of adult Tc1 mice, (a new mouse model for DS containing a human chromosome 21 and showing a range of features, including changes in behaviour, synaptic plasticity, cerebellar neuronal number, heart development and facial skeletal abnormalities, O’Doherty et al. Science 2005), as well as Ts1Cje mice, a segmental mouse trisomy model of DS. Using the panel of segmentally trisomic transchromosomic ES cells, the suppression of REST was mapped to a segment containing 10 HSA21 genes. Furthermore, using genome-wide quantitative trait locus (QTL) analysis of REST mRNA levels in lymphoblastoid cell lines from CEPH pedigrees, we identify a 3 Mb HSA21 segment as the most significant QTL controlling REST expression. The REST controlling region overlaps by 3 genes with the minimal region responsible for REST suppression in ES cells. Efforts using siRNA are underway to examine if the effects can be attributed to a single HSA21 gene. We also show that REST downregulation alone is sufficient to slow down in vitro neuronal differentiation of ES cells. As coordinated transcriptional activation of REST target genes is both necessary and sufficient for transition from pluripotent ES cells to neural progenitors and onwards to mature neurons, the persistent reduction of REST expression in trisomy 21 could cause some of the DS neural phenotypes.

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