Epigenetic control of gene expression.

A. Razin*, R. Shemer

*Corresponding author for this work

Research output: Contribution to journalReview articlepeer-review

24 Scopus citations
Original languageAmerican English
Pages (from-to)189-204
Number of pages16
JournalResults and Problems in Cell Differentiation
StatePublished - 1999

Bibliographical note

Funding Information:
Tomas J. Ekström Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden Dear Reader, During the past few years, the scientific community has experienced an explosion of interest and dedication to epigenetic research. Transcriptional mechanisms were previously analyzed from the naked DNA point of view, but studies today aimed at understanding genome function in a chromatin context is not only acknowledged, but also a requirement. Chromatin is the physical structure in which our genome functions in a regulated and highly organized fashion. It is interesting to observe how this focus has spread also to the general public. The reason for this is undoubtedly that increased epigenetic knowledge has provided molecular tools to study the interaction between the genome and the environment. This relationship has long been recognized, but has previously suffered from lack of molecular study due to limited theoretical bases as well as methodological shortcomings. Epigenetics is simply defined as the study of heritable properties in genome function, which is not directly dependent on the DNA primary sequence. This infers that information present with DNA, but not embedded in the primary sequence, can be transferred from a dividing cell to the daughter cells, making them acquire the same function as the mother cell, hence the heritability. The transferred cell identity can be seen as a memory of cell function and phenotype. The epigenetic mechanisms thus set an epigenomic “landscape” made up of modifications of histones and DNA, specific to a locus and to a particular cell type. These modifications which may be temporally, spatially and cooperatively interdependent, specify phenotype and cell-type specific responses. Temporally, since they are different throughout a cell-lineage differentiation and partially dynamic in the differentiated state; spatially, since the modifications are different throughout the genome; and cooperatively dependent, since one modification in a given locus may influence the appearance or presence of another one. In this way, the epigenomic landscapes formed are different for all cell-types. In contrast to the DNA primary sequence, the epigenomes of our cells have a life cycle encompassing changes starting from the gametes, to the fertilized egg, to the different cell types of the embryo, and to the adult individual. Some changes continue as we get old and disabled. The current issue in BBA General Subjects presents a number of reviews on epigenetics. In contrast to most other review compilations, this one focuses on a wide scope ranging from molecular mechanisms and epigenetic analyses, to epigenetics in relation to human disease and behavior. Since the epigenome is unique for each cell-type, and maybe even for each individual cell, this makes it extremely difficult to perform most human epigenetic analyses because the tissue of interest must be obtained for the respective study, e.g. hippocampus for behavior studies, or prefrontal cortex for schizophrenia. Therefore, some investigations must rely on autopsy material. Hence, autopsy material contributes to the difficulty in analyzing histone modifications or DNA/transcription factor interactions since these are unstable in nature and rely on intact chromatin. Nevertheless, surrogate tissues may sometimes be used to analyze DNA-methylation which is readily more available. Ammerpohl et al. describe numerous methods for interrogating the so-called 5 th base, 5-methylcytosine, from a global as well as regional and gene-specific perspective and point out the advantages and disadvantages of the different techniques. Lennartsson and Ekwall highlight the patterns of the histone code, and its involvement in cell differentiation and cancer. Histone modifications can be seen as patterns or clusters of specific combination of modifications found in both active and inactive genes of particular functional groups. These authors also explore the interesting semantic discussion on the definition of the term “epigenetics”, which includes the requirement of heritability through cell divisions. They argue that histone modifications are also heritable, based on studies with e.g. synchronized cells. The review by Joel Kleinman's team on epigenetics in schizophrenia, highlights the current knowledge and importance of the gene/environment interaction and the possible impact that epigenetic modifications of several key genes have on the understanding of the etiology of schizophrenia, and possible future remedies relying on epigenetic drugs. The impact by the environment in early life on epigenetic marks, with adult phenotypic consequences such as disease, stress handling or altered behavior is described by Moshe Szyf. This is interesting and important in light of the “cellular identity” or “memory” which is central in epigenetics. Epigenetic modifications created in early life may thus be sustained over many years, and can have effects on gene regulation in adult life. Turunen, Aavik and Ylä-Herttuala give an overview of the current epigenetic knowledge in atherosclerosis. Histone modification data in human disease are poorly researched, likely due to the problems obtaining biological material mentioned above. On the other hand, DNA-methylation of several key genes has been investigated and the connection between inflammation, homocystein, and disease appears to be evident. Ingrosso and Perna's review describes the close association between atherosclerosis, homocystein, and the uremic milieu involving DNA-methylation, as risk factors for cardiovascular disease. DNA-methylation and its relation to the metabolism of the methyl donor S -adenosylmethionine and its eventual product, homocysteine, suggest that diet involving folate may be a way to influence DNA-methylation and the risk for disease. It is of fundamental importance for clinical application of stem cells to understand how the gene programs of stemness and the differentiated states are regulated. In stem cell maintenance and differentiation, the poised mode made up by specific histone modifications and the so-called bivalent switch are important, and so is gene activity in relation to methylation. In the review by Phillipe Collas, the reader is informed about the potentially therapeutically important embryonic stem cells and mesenchymal stem cells and how they are regulated by epigenetics and chromatin states. It appears that the methylation pattern of a relatively small number of developmentally controlled genes such as OCT4 and NANOG may regulate epigenetic marks unique to human embryonic stem cells. The importance of mechanisms behind cellular differentiation also becomes evident for understanding the fundamentals of the immune system. Janson, Winerdal and Winqvist explain how epigenetic mechanisms provide the necessary dynamic control system for T helper cell development. An imperfect epigenetic regulation of cytokines during T-lymphocyte differentiation may explain conditions like autoimmunity and allergy. The function of epigenetic modifications and their functional consequences must always be viewed in the context of both already established epigenetic landscapes and the cell niche/milieu which may alter this balance. In their review, Huang and colleagues explain that such interaction exists, e.g. between breast cancer cells and its environment, including the extracellular matrix which can affect the variety of cancer cell/tumor behavior. Sophie Lelievre brings this question to a different level by emphasizing, not only the importance of intracellular signaling for epigenetic responses, but also the consequences of tissue architecture and mechanical transduction of signals affecting cell nuclear organization and epigenetic gene transcription control. The review by Chandrasekhar Kanduri's group highlights an important feature of the functional genome, the non-coding RNA (ncRNA) and its role in epigenetic regulation. As pointed out by the authors, while only a fraction of the genome codes for proteins, a much larger part is still transcribed. At least some of this is likely transcribed into ncRNA which is involved in regulating gene promoters or larger chromatin domains. It is also important when performing DNA-methylation studies to realize that methylation of a gene locus may actually silence an antisense RNA that negatively controls a gene in the opposite direction, and thereby causing a non-intuitive activation. The epigenetic research field is expanding, not only in number of publications, but also in awareness of its importance for understanding the whole concept of biology, including cellular morphology and interactions, disease and organismal behavior. I hope that this special issue on “Epigenetic control of gene expression” will give the reader an insight into this exciting concept of regulation of life. Tomas J. Ekström, professor of Molecular Cellbiology at the Department of Clinical Neuroscience, Karolinska Institutet, group leader for the Medical Epigenetics group at the Center for Molecular Medicine, Karolinska Hospital. Dr. Ekström took his Ph.D. in Biochemistry at the Stockholm University in 1987 with professor Gustav Dallner. He then spent nearly 3 years as a post doc at the Department of Pharmacology,University of California at San Diego, with professor Palmer Taylor, studying the transcriptional regulation of the acetylcholine esterase gene. At his return to Sweden in 1990, he became interested in the human insulin-like growth factor 2 gene and its regulation and genomic imprinting in development and cancer. A number of important papers on imprinting and epigenetics were produced in the following years. In 1997, Dr. Ekström was awarded a senior researcher position from the Swedish Cancer Foundation, and in 2002, he became professor at Karolinska Institutet. His primary interest today is the epigenetic etiology of malignant brain tumors, where mechanisms behind altered DNA-methylation is in focus. Dr. Ekström is a nationally and internationally frequently requested lecturer on epigenetics, both by laymen and professionals, and his expertise in epigenetics has created active national and international collaborations in a wide spectrum of disciplines with researchers in oncology, neuro-psychopharmacology, nephrology, virology, pediatrics, geriatrics, and physiology.

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