Preface

It is more evident now than ever before that dynamic organization of human genome into nucleoprotein structure, chromatin confers the unique regulatory mechanisms for most of the cellular phenomena, which include replication, transcription, DNA repair, recombination and also apoptosis. The dynamic nature of the chromatin is regulated by chromatin modifications (epigenetic alterations), remodeling, histone chaperones and functional interactions of different chromatin interacting non-histone proteins. Dysfunction of this highly inter connected machineries disturb the cellular homoeostasis, and thereby causes several diseases. As we advance in our knowledge of chromatin function and also disease mechanisms in more details, their causal relationship is becoming more evident. This has lead to the identification of chromatin function as target for new generation therapeutics. In the light of these advances, it happens to be the right time to explore current insights into various aspect of chromatin and disease connection under one cover.

Authors who are actively involved in chromatin research and have made several original contributions to develop latest paradigms in the field have written the chapters of this book. Significantly, the authors' repertoire is truly international. They come from eight different countries of Asia, Europe and America. The book has been divided into three different parts. Part I introduces the reader to the dynamic nature of chromatin structure and its link to diseases. First two chapters in this part deal with the chromatin architecture, chromatin dynamics in the cell cycle and molecular mechanism of chromatin remodeling. The next chapter describes the role of Poly (ADP-Ribose) Polymerase-1(PARP-1) in the regulation of chromatin structure and transcription in response to specific cellular signals. This chapter also highlights the potential therapeutic use of drug that target PARP-1's enzymatic activity for the treatment of diseases. The incorporation of histone variants (non-allelic form of conventional histones) within a nucleosome could affect the overall nucleosome structure and generate a non-canonical nucleosome particle with novel properties. Following two chapters discuss the mechanism of histone variant exchange, the unusual structure of the chromatin domains containing histone variants, their functional significance as epigenetic markers and link to congenital anomalies (cancer and other diseases). Recent research has indicated that histone chaperones play a major role in the chromatin dynamics, ranging from replication dependent histone deposition to the replication independent histone exchange or removal. Therefore, we have included two, chapters expanding the present understanding of histone chaperones with an emphasis upon their involvement in cancer and other diseases. In the last chapter of this part, the importance of the chromatin structure and dynamics has been discussed in connection with the mode of action of DNA binding chemotherapeutic drugs.

A broader definition of chromatin is not limited to being a complex of histones and DNA, rather it is a dynamic organization of histone, DNA, RNA and rapidly interacting non-histone chromatin associated proteins (CAPs). Post translational modifications of non histone chromatin proteins, therefore dramatically alter the chromatin structure-function. The first chapter of the Part II, describes the role of reversible acetylation of non histone proteins (several of which are also component of chromatin) in cellular function and disease. Chromatin is compartmentalized into various domains by a series of loops tethered onto the base of nuclear matrix. Scaffold or Matrix Attachment Regions (S/MAR) punctuate these attachment sites and govern the nuclear architecture by establishing chromatin boundaries. The second chapter of Part II, enumerates the role of MARs and MAR binding proteins in the alteration of local chromatin structure during transcription regulation, viral integration and also disease manifestation.

Part III focuses on the epigenetic modifications of chromatin that are linked to disease and also the development of putative therapeutic approaches which are not far from reality. Reversible acetylation is one of the most widely studied chromatin modifications involved in the regulation of several cellular phenomena. Dysfunction of histone acetyltransferases and deacetylases lead to several diseases (Chapter 11) ranging from neurodegenerative diseases to cancer (Chapters 11, 12 and 13). Therefore small molecule modulators (activator and inhibitors) of HATs and HDACs are now being recognized as potential therapeutic tools (Chapter 12). Apart from acetylation, rapidly increasing number of literature suggest that phosphorylation of histones plays a pivotal role in regulation of acetylation and thereby transcription and DNA repair. Aberrant histone phosphorylation and histone kinases activity are often associated with diseases (Chapter 14 ). Histone methylation is one of the most versatile and stable epigenetic markers. In Chapter 15 the repressive chromatin marker, H3K9 methylation has been discussed. The role of chromatin modifications including methylation in the regulation of tumor suppressor p53 function has been discussed in Chapter 16. Chromatin remodeling and modifications (acetylation, methylation and phosphorylation) are essential for the gene expression of human genome integrated HIV. Therefore, the modifying enzymes could be the target for combinatorial therapy (Chapter 17). Apart from discussing each of the posttranslational modification in connection to disease manifestation, Chapter 18 also high lights the possible therapeutic approaches targeting enzymes involved in the process of modifications.

In writing and editing the chapters we have put our best effort to make the materials accessible to the scientist not familiar with the chromatin field and to students those who are beginning their career. We hope that this book will provide a stimulating overview for investigators who are working in the field and as well as scientists in related fields (e.g. Virology, Neurobiology, Chemical Biology,

Pharmaceutical Chemistry and Nanobiology). We also hope that this book attracts the pharmaceutical industry, who can utilize the knowledge of chromatin dynamics and its link to disease for the betterment of mankind. We thank all the authors for their outstanding contributions in preparing this book and also Ashok Reddy and Marie Johnson for helping in the processing of the manuscript and all the correspondence.

J N Centre For Advanced Scientific Research T.K.K.

Jakkur PO

Bangalore-64

Biophysics Division DD

Saha Institute of Nuclear Physics Bidhannagar, Kolkata - 700 064 June, 2006

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