Telomere shortening in normal human cells causes replicative senescence, a p53-dependent growth arrest state, which is thought to represent an innate defence against tumour progression. However, although it has been postulated that critical telomere loss generates a 'DNA damage' signal, the signalling pathway(s) that alerts cells to short dysfunctional telomeres remains only partially defined.
The Journal of Neuroscience: The Official Journal of the Society for Neuroscience
Spinal muscular atrophy (SMA), a recessive neurodegenerative disease, is characterized by the selective loss of spinal motor neurons. No available therapy exists for SMA, which represents one of the leading genetic causes of death in childhood. SMA is caused by a mutation of the survival-of-motor-neuron 1 (SMN1) gene, leading to a quantitative defect in the survival-motor-neuron (SMN) protein expression. All patients retain one or more copies of the SMN2 gene, which modulates the disease severity by producing a small amount of stable SMN protein.
The human tyrosine hydroxylase (hTH) gene has a 42†bp evolutionarily conserved region designated (CR) II at -7.24†kb, which bears 93% homology to the region we earlier identified as containing the glucocorticoid response element, a 7†bp activator protein-1 (AP-1)-like motif in the rat TH gene. We cloned this hTH-CRII region upstream of minimal basal hTH promoter in luciferase (Luc) reporter vector, and tested glucocorticoid responsiveness in human cell lines.
Human neurons are functional over an entire lifetime, yet the mechanisms that preserve function and protect against neurodegeneration during ageing are unknown. Here we show that induction of the repressor element 1-silencing transcription factor (REST; also known as neuron-restrictive silencer factor, NRSF) is a universal feature of normal ageing in human cortical and hippocampal neurons. REST is lost, however, in mild cognitive impairment and Alzheimer's disease.
Chronic neuropsychiatric illnesses such as schizophrenia, bipolar disease and autism are thought to result from a combination of genetic and environmental factors that might result in epigenetic alterations of gene expression and other molecular pathology. Traditionally, however, expression studies in postmortem brain were confined to quantification of mRNA or protein. The limitations encountered in postmortem brain research such as variabilities in autolysis time and tissue integrities are also likely to impact any studies of higher order chromatin structures.
We have recently shown that the expression of spermidine/spermine N1-acetyltransferase (SAT1) is downregulated across the brains of suicide completers, and that its expression is influenced by genetic variations in the promoter. Several promoter polymorphisms in SAT1, including rs6526342, have been associated with suicide and other psychiatric disorders, and display haplotype-specific effects on expression. However, these effects cannot explain total variability in SAT1 expression, and other regulatory mechanisms, such as epigenetic factors, may also be at play.
The International Journal of Neuropsychopharmacology
The synapsin family of neuronal phosphoproteins is composed of three genes (SYN1, SYN2 and SYN3) with alternative splicing resulting in a number of variants with various levels of homology. These genes have been postulated to play significant roles in several neuropsychiatric disorders, including bipolar disorder, schizophrenia and epilepsy. Epigenetic regulatory mechanisms, such as histone modifications in gene regulatory regions, have also been proposed to play a role in a number of psychiatric disorders, including bipolar disorder and major depressive disorder.
Histone deacetylases (HDACs) compact chromatin structure and repress gene transcription. In schizophrenia, clinical studies demonstrate that HDAC inhibitors are efficacious when given in combination with atypical antipsychotics. However, the molecular mechanism that integrates a better response to antipsychotics with changes in chromatin structure remains unknown.
Mis-regulation of gene expression due to epigenetic abnormalities has been linked with complex genetic disorders, psychiatric illness, and cancer. In addition, the dynamic epigenetic changes that occur in pluripotent stem cells are believed to impact regulatory networks essential for proper lineage development. Chromatin immunoprecipitation (ChIP) is a technique used to enrich genomic fragments using antibodies against specific chromatin modifications, such as DNA-binding proteins or modified histones.
To investigate epigenetic contributions to Huntington's disease (HD) pathogenesis, we carried out genome-wide mapping of the transcriptional mark, trimethyl-histone H3-lysine 4 (H3K4me3) in neuronal nuclei extracted from prefrontal cortex of HD cases and controls using chromatin immunoprecipitation followed by deep-sequencing.