Therapeutics development for triplet repeat expansion diseases

The underlying genetic mutations for many inherited neurodegenerative disorders have been identified in recent years. One frequent type of mutation is trinucleotide repeat expansion. Depending on the location of the repeat expansion, the mutation might result in a loss of function of the disease gene, a toxic gain of function or both. Disease gene identification has led to the development of model systems for investigating disease mechanisms and evaluating treatments. Examination of experimental findings reveals similarities in disease mechanisms as well as possibilities for treatment.     

Chromatin remodeling in plants

In the past two years, a variety of forward genetic screens have revealed predicted plant chromatin remodeling components that are involved in either differential histone acetylation or ATP-dependent SWI2/SNF2-related complexes. Combined with the results of recent reverse genetic studies, these findings have begun to provide the groundwork for determining the function of chromatin-based control in plants.     

Modeling diseases of noncoding unstable repeat expansions using mutant pluripotent stem cells

Pathogenic mutations involving DNA repeat expansions are responsible for over 20 different neuronal and neuromuscular diseases. All result from expanded tracts of repetitive DNA sequences (mostly microsatellites) that become unstable beyond a critical length when transmitted across generations. Nearly all are inherited as autosomal dominant conditions and are typically associated with anticipation. Pathologic unstable repeat expansions can be classified according to their length, repeat sequence, gene location and underlying pathologic mechanisms. This review summarizes the current contribution of mutant pluripotent stem cells (diseased human embryonic stem cells and patient-derived induced pluripotent stem cells) to the research of unstable repeat pathologies by focusing on particularly large unstable noncoding expansions. Among this class of disorders are Fragile X syndrome and Fragile X-associated tremor/ataxia syndrome, myotonic dystrophy type 1 and myotonic dystrophy type 2, Friedreich ataxia and C9 related amyotrophic lateral sclerosis and/or frontotemporal dementia, Facioscapulohumeral Muscular Dystrophy and potentially more. Common features that are typical to this subclass of conditions are RNA toxic gain-of-function, epigenetic loss-of-function, toxic repeat-associated non-ATG translation and somatic instability. For each mechanism we summarize the currently available stem cell based models, highlight how they contributed to better understanding of the related mechanism, and discuss how they may be utilized in future investigations.     

Chromatin remodeling in mammalian zygotes.

With sperm-egg fusion at the time of fertilization the gamete nuclei are remodeled from genetically quiescent structures into pronuclei capable of DNA synthesis. Features of this process that are critical to insure the genetic integrity of the zygote and the success of subsequent embryonic development include: oocyte responses that prevent polyspermy; completion of the 2nd meiotic division by the oocyte; exchange of proteins in the sperm nucleus; and, remodelling of the oocyte chromosomes and sperm nucleus into functional pronuclei. Elucidation of the biological and molecular mechanisms underlying zygote formation and chromatin remodeling should enhance our understanding of the potential vulnerability of the zygote to toxicant-induced damage.     

Chromatin remodeling in development and differentiation

During development and differentiation, early inductive processes that influence cell fate at a later stage leave marks at distinct gene loci that are maintained through several rounds of mitosis. The structure of chromatin is part of this epigenetic memory that restricts or permits differential expression of genes in descendant cells. Establishing a cell-type-specific chromatin pattern thus predestines future cell differentiation and deters cell-lineage infidelity, as it often occurs during neoplastic transformation. As such, understanding the dynamics and mechanisms underlying chromatin remodeling has been a major focus of recent molecular genetic research that holds great promise for biomedical discoveries.     

Chromatin remodeling and genome stability

A report on the 12th Tenovus Scotland Symposium 'Stability and Regulation of Genes and Genomes', Glasgow UK, 6-7 April 2006.     

Chromatin remodeling and human disease

In the past few years, there has been a nascent convergence of scientific understanding of inherited human diseases with epigenetics. Identified epigenetic processes involved in human disease include covalent DNA modifications, covalent histone modifications, and histone relocation. Each of these processes influences chromatin structure and thereby regulates gene expression and DNA methylation, replication, recombination, and repair. The importance of these processes for nearly all aspects of normal growth and development is illustrated by the array of multi-system disorders and neoplasias caused by their dysregulation.     

Tetraplex formation by the progressive myoclonus epilepsy type-1 repeat: implications for instability in the repeat expansion diseases

The repeat expansion diseases are a group of genetic disorders resulting from an increase in size or expansion of a specific array of tandem repeats. It has been suggested that DNA secondary structures are responsible for this expansion. If this is so, we would expect that all unstable repeats should form such structures. We show here that the unstable repeat that causes progressive myoclonus epilepsy type-1 (EPM1), like the repeats associated with other diseases in this category, forms a variety of secondary structures. However, EPM1 is unique in that tetraplexes are the only structures likely to form in long unpaired repeat tracts under physiological conditions.     

Chromatin remodeling and Rb activity

Progression of cells through the cell cycle is central to normal cell proliferation, and checkpoints that regulate this cycle are targets of tumorigenic mutations. One of these checkpoints is the Rb family of proteins that seems to regulate exit of cells from both G(1) and S phase of the cell cycle. Recent studies have linked the function of the Rb family to chromatin remodeling enzymes.