Chromatin remodeling in neural stem cell differentiation

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Chromatin remodeling is a dynamic alteration of chromatin structure that regulates several important biological processes. It is brought about by enzymatic activities that catalyze covalent modifications of histone tail or movement of nucleosomes along the DNA, and these activities often require multisubunit protein complexes for its proper functions. In concert with DNA methylation and noncoding RNA-mediated processes, histone modification such as acetylation and methylation regulates gene expression epigenetically, without affecting DNA sequence. Recent advances have revealed that this intrinsic regulation, together with protein complexes such as RE1 silencer of transcription/neuron-restrictive silencer factor (REST/NRSF) and switch/sucrose nonfermentable (SWI/SNF), play critical roles in neural stem cell fate determination.

Introduction

Differentiated cells in the nervous system are generated from common neural stem cells (NSCs) which possess the ability to self-renew and to give rise to the three major cell types: neurons, astrocytes, and oligodendrocytes. During development, the fate of NSCs is orchestrated both by intrinsic programs operating within the cells and by cues arriving from outside the cells. Epigenetic mechanisms, such as DNA methylation, histone modification, and noncoding RNA-mediated processes, are examples of these intrinsic programs, which can generate variable patterns of gene expression from an invariant regulatory DNA sequence. Meanwhile, extrinsic molecules such as cytokines and growth factors can bind to their cognate receptors on the cell surface and transduce their signals into the cell. These signals are eventually integrated into existing transcription factor (TF) regulatory networks that control gene expression. Recent advances have revealed that, in order to progress to a subsequent stage of development, cells along the neural lineage can use components of both intrinsic and extrinsic environments to alter their chromatin structure, thereby either enhancing or repressing gene expression. This regulated alteration of chromatin structure is called chromatin remodeling. Here we discuss new insights into the mechanisms that underlie chromatin remodeling, and its significance in determining NSC fate.

Section snippets

Histone modification

Chromatin structure can be dynamically changed by covalent modifications that take place on histones. These modifications display a level of diversity and complexity whose combinatorial existence is read out as a ‘code’ for accessible/active chromatin (euchromatin) or condensed/inactive chromatin (heterochromatin) states [1]. In particular, two of the core histones, H3 and H4, have long amino-terminal tails that protrude from the nucleosome and are subject to an array of post-translational

Role of REST/NRSF and SWI/SNF

The recognition that multisubunit protein complexes are recruited to numerous genes during regulation of their expression has sparked intense efforts to characterize the complexes and their specific functions. Interestingly, although some of these proteins do not bind directly to DNA, they possess chromatin structure-modifying capacities that can lead to either permission or restriction of its target gene's transcription.

In ESCs and non-neuronal cells, neuronal genes are repressed by the

Conclusions

It is now well established that chromatin remodeling plays a substantial role in the differentiation of NSCs. Combinatorial and cell type specific regulation of subunit composition also emerged as a crucial factors to control targeting and function of chromatin remodeling complexes during neural differentiation. However, our understanding about this relationship is still in its infancy and many interesting avenues remain to be explored. For example, it is unclear why a global increase of

References and recommended reading

Papers of particular interest, published within the period of review, have been highlighted as:

  • • of special interest

  • •• of outstanding interest

Acknowledgements

We apologize to colleagues whose work we may not have been able to include in this review due to space constraints. We thank our laboratory members for useful discussions on this topic, and Ian Smith for critical reading of the manuscript. We have been supported by a Grant-in-Aid for Scientific Research on Priority Areas-Molecular Brain Research and the NAIST Global COE Program (Frontier Biosciences: Strategies for Survival and Adaptation in a Changing Global Environment) from the Ministry of

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