Progress in drug research. Fortschritte der Arzneimittelforschung. Progres des recherches pharmaceutiques最新文献

Epigenetic alterations in cancer include changes in DNA methylation and associated histone modifications that influence the chromatin states and impact gene expression patterns. Due to recent technological advantages, the scientific community is now obtaining a better picture of the genome-wide epigenetic changes that occur in a cancer genome. These epigenetic alterations are associated with chromosomal instability and changes in transcriptional control which influence the overall gene expression differences seen in many human malignancies. In this review, we will briefly summarize our current knowledge of the epigenetic patterns and mechanisms of gene regulation in healthy tissues and relate this to what is known for cancer genomes. Our focus will be on DNA methylation. We will review the current standing of technologies that have been developed over recent years. This field is experiencing a revolution in the strategies used to measure epigenetic alterations, which includes the incorporation of next generation sequencing tools. We also will review strategies that utilize epigenetic information for translational purposes, with a special emphasis on the potential use of DNA methylation marks for early disease detection and prognosis. The review will close with an outlook on challenges that this field is facing.

Transcriptional regulation is one of the most fundamental processes in biology, governing the morphology, function, and behavior of cells and thus the survival of organisms. The embryonic stem cell (ESC) provides a good model for the understanding of transcriptional regulation in vertebrate systems. Recent efforts have led to the identification of molecular events, which confer upon these cells the unique properties of pluripotency and self renewal. The core regulatory network maintaining the ESC identity involves three master regulators: Oct4, Sox2, and Nanog. Large-scale mapping studies interrogating the binding sites of these and other transcription factors showed co-occupancy of distinct sets of transcription factors. The assembly of multitranscription factor complexes could serve as a mechanism for providing specificity in regulating ESC-specific gene expression. These studies are also beginning to unravel the transcriptional regulatory networks that govern the ESC identity. Loss-of-function RNAi screens also identified novel regulatory molecules involved in the stable propagation of the ESC state. This argues for an ESC transcriptional regulation program in which interconnected transcriptional regulatory networks involving large numbers of transcription factors and epigenetic modifiers work in concert on ESC- and differentiation-specific genes to achieve cell state stability. This chapter traces the major efforts made over the past decade in dissecting the transcriptional regulatory network governing ESC identity and offers perspectives on the future directions of the field.

DNA methylation acts in concert with other epigenetic mechanisms to regulate normal gene expression and facilitate chromatin organization within cells. Aberrant DNA methylation patterns are acquired during carcinogenic transformation; such events are often accompanied by alterations in chromatin structure at gene regulatory regions. The expression pattern of any given gene is achieved by interacting epigenetic mechanisms. First, the insertion of nucleosomes at transcriptional start sites prevents the binding of the transcriptional machinery and additional cofactors that initiate gene expression. Second, nucleosomes anchor all of the DNMT3A and DNMT3B methyltransferase proteins in the cell, which suggests a role for histone octamers in the establishment of DNA methylation patterns. During carcinogenesis, epigenetic switching and 5-methylcytosine reprogramming result in the aberrant hypermethylation of CpG islands, reducing epigenetic plasticity of critical developmental and tumor suppressor genes, rendering them unresponsive to normal stimuli. Here, we will discuss the importance of both established and novel molecular concepts that may underlie the role of DNA methylation in cancer.

Mental retardation is a common form of cognitive impairment affecting approximately 3% of the population in industrialized countries. The mental retardation syndrome incorporates a highly diverse group of mental disorders characterized by the combination of cognitive impairment and defective adaptive behavior. The genetic basis of the disease is strongly supported by identification of the genetic lesions associated with impaired cognition, learning, and social adaptation in many mental retardation syndromes. Several of the impaired genes encode epigenetic regulators of gene expression. These regulators exert their function through genome-wide posttranslational modification of histones or by mediating and/or recognizing DNA methylation. In this chapter, we review the most recent advances in the field of epigenetic mechanisms of mental retardation. In particular, we focus on animal models of the human diseases and the mechanism of transcriptional deregulation associated with changes in the cell epigenome.

Maintenance of normal cell growth and differentiation is highly dependent on coordinated and tight transcriptional regulation of genes. In cancer, genes encoding growth regulators are abnormally expressed. Particularly, silencing of tumor suppressor genes under the control of chromatin modifications is a major underlying cause of unregulated cellular proliferation and transformation. Thus mechanisms, which regulate chromatin structure and gene expression, have become attractive targets for anticancer therapy. Histone deacetylases are enzymes that modify chromatin structure and contribute to aberrant gene expression in cancer. Research over the past decade has led to the development of histone deacetylase inhibitors as anticancer agents. In addition to their effect on chromatin and epigenetic mechanisms, HDAC inhibitors also modify the acetylation state of a large number of cellular proteins involved in oncogenic processes, resulting in antitumor effects. The current monograph will review the role of histone deacetylases in protumorigenic mechanisms and the current developmental status and prospects for their inhibitors in cancer therapy.

MicroRNAs (miRNAs) are small noncoding RNAs that regulate the expression of a large fraction of genes in animals, plants, and protozoa. miRNA-mediated gene repression occurs posttranscriptionally, generally by base-pairing to the 3'-untranslated regions of target mRNAs, which inhibits protein synthesis and destabilizes the mRNA. In this chapter, we discuss the biological functions of miR-122, a highly abundant, liver-specific miRNA. We will review how studies of miR-122 helped to establish important new paradigms of miRNA-mediated regulation, as well as identifying miR-122 as a factor implicated in important human diseases, including cancer and hepatitis C. We discuss antisense strategies targeting miR-122 as a potential therapeutic approach to treat hepatitis C and possibly other diseases.

Many studies have demonstrated that covalent histone modifications are dynamically regulated to cause both chemical and physical changes to the chromatin template. Such changes in the chromatin template lead to biologically significant consequences, including differential gene expression. Histone lysine methylation, in particular, has been shown to correlate with gene expression both positively and negatively, depending on the specific site and degree (i.e., mono-, di-, or tri-) of methylation within the histone sequence. Although genetic alterations in the proteins that establish, or "write," methyl modifications and their effect in various human pathologies have been documented, connections between the misregulation of proteins that remove, or "erase," histone methylation and disease have emerged more recently. Here we discuss three mechanisms through which histone methylation can be removed from the chromatin template. We describe how these "erasure" mechanisms are linked to pathways that are known to be misregulated in diseases, such as cancer. We further describe how errors in the removal of histone methylation can and do lead to human pathologies, both directly and indirectly.

In Eukarya, the packaging of DNA into chromatin provides a barrier that allows for regulation of access to the genome. Chromatin is refractory to processes acting on DNA. ATP-dependent chromatin remodeling machines and histone-modifying complexes can overcome this barrier (or strengthen it in silencing processes). Both components of chromatin (DNA and histones) are subject to postsynthetic covalent modifications, including methylation of lysines (the focus of this chapter). These lysine marks are generated by a host of histone lysine methyltransferases (writers) and can be removed by histone lysine demethylases (erasers). Importantly, epigenetic modifications impact chromatin structure directly or can be read by effector regulatory modules. Here, we summarize current knowledge on structural and functional properties of various histone lysine methyltransfereases and demethylases, with emphasis on their importance as druggable targets.

Acute leukemia is characterized by clonal expansion of hematopoietic stem and progenitor cells with blocked differentiation. Clinical and experimental evidences suggest that acute myeloid leukemia (AML) is the product of several functionally cooperating genetic alterations including chromosomal translocations leading to expression of leukemogenic fusion proteins. Several AML-associated lesions target chromatin regulators like histone methyltransferases or histone acetyltransferases, including mixed-lineage leukemia 1 (MLL1) or CREB bindung protein/p300. Molecular and biochemical studies start to provide useful insights into the mechanisms of targeting and mode-of-action of such leukemogenic fusion proteins resulting in aberrant gene expression programs and AML. Chromatin modulating mechanisms are also mediating the transforming activity of key drivers of leukemogenesis by aberrant recruitment of corepressors. Recent large-scale screening efforts demonstrated that both aberrant DNA promoter methylation and aberrantly expressed microRNAs play an important role in the pathogenesis of AML as well. Current efforts to therapeutically exploit the potential reversibility of epigenetic mechanisms are focused on small molecules that inhibit DNA methyltransferases or histone deacetylases. Several phase I/II clinical trials using such compounds have reported promising, but mostly transient, clinical responses. This underscores the need to further dissect the molecular players of epigenetic mechanisms driving induction, maintenance, and potential reversibility of leukemic state to develop efficient and long-lasting targeted therapeutic strategies.