Tag Archives: Epigenetics

A protein complex called Polycomb Repressive Complex 2 (PRC2), which plays a critical role in forming specific classes of nerve cells in the brain during development, also plays an important role in the adult brain where it may contribute to Huntington’s disease and other neurodegenerative disorders, according to a study published in the journal Nature Neuroscience.

The study focuses on epigenetics, the study of changes in the action of human genes caused by molecules that regulate when, where, and to what degree our genetic material is activated. Protein complexes have an important role in the biochemical processes that are associated with the expression of genes. Some help to silence genes, whereas others are involved in the activation of genes. The importance of such complexes is emphasized by the fact that mice cannot live if they do not possess PRC2.

In the striatum, the brain region that regulates voluntary movements, the majority of neurons are called medium spiny neurons (MSNs), so-called because of their spiny appearance. MSNs are further characterized by the expression of a specific set of genes that determines their unique identity and function. Once specified, an MSN’s identity needs to be maintained throughout life in order to ensure normal motor function.

PRC2 is an epigenetic gene regulator that represses or silences a given gene’s expression. While previous research has found PRC2 to be critical for normal brain development, the role of this protein complex in maintaining the specialization and function of adult MSNs had remained a mystery.

To study the role of PRC2 in MSN formation and function, the researchers generated a mouse model that lacks the PRC2 complex specifically in neurons in the forebrain. The research team found that neurons in mice that lack PRC2, including mice that lacked PRC2 in MSNs, showed inappropriate reactivation of genes that are usually turned off in these cells, and inhibited the expression of genes that are usually turned on and which are essential to the MSN’s specific function. The data suggests that PRC2 not only governs the process of brain cell development but also that PRC2 helps to maintain MSNs’ identity into the animal’s adult life and plays an active role in determining whether the neuron should live or die.

Closer examination of the altered genes in the striatum of the mice that lacked PRC2 revealed that many of these genes controlled by PRC2 are those known to control the process whereby brain cells self-destruct. Consistent with this finding, the PRC2-lacking mice showed signs of progressive cell death in the striatum and had smaller brain mass then non-mutant mice. In addition, these mice developed a progressive and fatal neurodegenerative disorder reminiscent of Huntington’s disease in humans, suggesting that disruption of PRC2 may contribute to neurodegenerative disorders.

Paper: “Polycomb repressive complex 2 (PRC2) silences genes responsible for neurodegeneration”
Reprinted from materials provided by Mount Sinai Hospital.

Beyond the four-letter alphabet of the genome, a far richer code dictates when and where genes are transcribed. The epigenome—defined by an ever-expanding list of modifications to DNA and the proteins that interact with it—determines which genes are dialed up or down and gives each cell type its unique personality. Thickening an already dense plot, three recent papers suggest that the brain may have its own epigenetic lingo.

One, published in Neuron on June 17, described the epigenome of three different types of neuron from the mouse brain—one excitatory, and two inhibitory. Among a slew of other findings, the study reported that neurons harbor a striking degree of cytosine methylation beyond the well-known cytosine-guanine (CpG) sites. This novel modification more closely correlated with gene expression and with neuronal phenotype than did the more common CpG methylation.

To generate a more detailed epigenetic map of neurons in the mouse brain, the researchers employed a technique called INTACT (isolation of nuclei tagged in specific cell types) to study nuclei from three types of neuron (see image above). The technique, which uses antibodies to capture nuclei expressing a protein tag, had been established in a plant model, and later used in flies, worms, and frogs, but never in mammals. INTACT isolates nuclei from homogenized tissue that is first frozen intact. This eliminates the need to first separate or sort the different types of cells, which can damage and/or activate neurons and confound results. INTACT allows researchers to obtain enough genetic material from specific cell types to run methylation and other epigenetic analyses.

Source:  AlzResearch Forum

Epigenetic modifications control gene expression, but scientists still don’t know if or how they contribute to disease. To address this knowledge gap, the National Institutes of Health launched the Roadmap Epigenomics Project in 2008 to compare epigenomes in healthy and diseased cells.

In the August 17 Nature Neuroscience, two papers from separate but collaborative research groups report on some of the fruits of that effort. Both groups surveyed DNA methylation in hundreds of human AD and control brains and identified several regions where changes in this epigenetic mark correlated with the amount of Alzheimer’s pathology. The results may help flag genes that are turned up or down in AD, and provide insight into pathogenesis, said Philip De Jager at Brigham and Women’s Hospital, Boston, the first author of one of the papers.