Chromatin Modification in Central Nervous System (CNS)

What is Chromatin Modification?

The primary resident of eukaryotic nuclei is the genetic material itself, packaged in the form of chromatin. Chromatin is composed of DNA, histones, and additional architectural proteins such as heterochromatin protein 1 (HP1). Although the core histones are bound relatively tightly to DNA, chromatin is maintained mainly by the dynamic association with its architectural proteins. In addition, histones are subject to a wide variety of post-translational modifications regulating chromatin accessibility and gene expression.

Chromatin can be classified as either euchromatin or heterochromatin. Euchromatin is typically marked with characteristic histone modifications such as histone H3 trimethylated on lysine 4 (H3K4me3) and H3 acetylated on lysine 9 (H3K9ac). Heterochromatin is marked by distinctive heterochromatic histone marks, including H3K9me3 and H4K20me3. An additional important chromatin mark is DNA methylation. Methylation occurs specifically on cytosines inside CpG dinucleotides and is usually associated with gene silencing. Heterochromatic regions, therefore, such as centromeric satellite repeats, are heavily methylated.

Fig.1 Heterochromatin in different CNS cell types. (Takizawa, 2008)

Mechanisms of Chromatin Regulation in Central Nervous System (CNS)

One of the critical functions for chromatin regulation in the brain involves tightly controlling gene expression patterns in a cell-type-specific manner during CNS development. The activities of histone-modifying enzymes mainly regulate local chromatin structure and function. Enzymes adding or removing these modifications play essential roles in regulating gene expression, and the addition and removal of all of these marks are dynamic. Changes in the post-translational modifications of histones, including acetylation, methylation, phosphorylation, and ubiquitination, are also important in regulating transcription.

• Histone Acetylation and Deacetylation

Hyperacetylation of histones following UV radiation is an identified chromatin modification associated with DNA damage. Histone acetylation plays a pivotal role in essentially all cell types; especially histone acetyltransferases (HATs) can be involved in neuronal processes. HAT activity is shown to participate in normal brain development and functions. Histone acetylation was also observed during the reestablishment of learning and memory during environmental enrichment in a mouse model of neurodegeneration. In addition, HAT activity is profoundly implicated in CNS-related diseases. For example, histone acetylation was shown to be inhibited by the action of caspases during apoptosis in both in vitro and in vivo models of neurodegeneration.

Recently, several studies have revealed the underappreciated roles of histone deacetylases (HDACs) in the early phases of DNA repair, and their roles are particularly relevant to neurodegeneration. HDAC regulation is involved in the differentiation of neural stem cells into oligodendrocytes and neurons, depending on the exact conditions and the precise differentiation stage. Still, it is also implicated in neuronal cell death. Histone acetylation has a crucial association with many neuronal processes in neurogenesis, neuronal proliferation, circadian rhythm, memory formation, and neuronal activity. Histone deacetylation is a major component of CNS functions in both health and disease and prompted HDAC inhibitors as potential therapeutic agents in CNS disorders.

Fig.2 Histone acetylation and deacetylation and HDAC inhibition. (Takizawa, 2008)

• Signal Transduction Controlling Histone Acetylation

The signal transduction processes controlling histone acetylation in the mature CNS are just beginning to be investigated. However, two signaling cascades have been implicated in controlling histone acetylation and chromatin structure in the mature CNS. One pathway is in the mitogen-activated protein kinase (MAPK) superfamily-exemplified by the ERK/MSK/CREB pathway. The phosphorylation and activation of CREB recruit CREB binding protein (CBP), which is a HAT that regulates local chromatin structure as part of CREB-dependent activation of nuclear gene transcription. The second known signaling pathway regulating chromatin structure in the mature CNS is the nuclear factor B (NFB) signaling pathway. NFB is a DNA-binding transcription factor that controls histone acetylation and chromatin structure in the CNS by mechanisms that are still being worked out. Thus, it is known at this point that both the ERK/MSK/CREB pathway and the IKK/NFB pathway actively regulate chromatin structure in the mature CNS.

• Histone methylation and demethylation

Unlike histone acetylation, the effects of histone methylation are dependent on the specific residue that is modified. Many studies implicate the involvement of histone methylation and demethylation in the CNS and call for further investigation of the mechanisms and proteins involved, especially as histone demethylation has only recently been discovered. For instance, disruption of the gene encoding euchromatin histone methyltransferase 1 (Eu-HMTase1), which methylates lysine 9 on histone H3 (H3K9), causes severe mental retardation and behavioral problems in patients, suggesting an imperative role in CNS development and function. In addition, altered neuronal histone methylation patterns are also associated with Huntington's disease. Post-mortem brains from Huntington's disease patients show increased levels of H3K9 methylation, and a mouse model of Huntington's disease shows elevated H3K9 methylation and increased levels of the H3K9 methyltransferase ESET.

Fig.3 Tail methylations (left) and acetylation (right) of histones H3 (top) and H4 (bottom). (Takizawa, 2008)

Chromatin Modification and Closure of Developmental Critical Periods

Recent findings have suggested a novel and exciting idea that the capacity for chromatin modification might be involved in switching off CNS cortical plasticity as a mechanism for closure of a critical developmental period. A recent article presents an interesting linkage between chromatin remodeling and experience-dependent plasticity in the visual cortex. In their work, the authors identified a new candidate signaling and transcriptional regulation mechanism in ocular dominance (OD) column developmental plasticity: ERK/MAPK-dependent regulation of histone modifications. Their work specifically suggested that one mechanism for closure of the critical period is uncoupling activity-dependent MAPK regulation from one of its targets, histone acetylation.

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Reference

1. Takizawa, T.; Meshorer, E. Chromatin and nuclear architecture in the nervous system. Trends in neurosciences. 2008, 31(7), 343-352.