Journal of Experimental and Integrative Medicine 2011; 1(3):139-147 www.jeim.org 139 Epigenetic mechanisms in human physiology and diseases Ahmet Korkmaz 1,2 , Lucien C. Manchester 2 , Turgut Topal 1 , Shuran Ma 2 , Dun-Xian Tan 2 , Russel J. Reiter 2 1 Department of Physiology, Gulhane Military Medical Academy, Ankara, Turkey. 2 Department of Cellular and Structural Biology, UT Health Science Center, San Antonio, Texas, USA. Abstract Although the sequence of human genome is known, our understanding of the complicated network that takes place inside cells is far from complete. Many questions still remain unanswered with the regard to how the complex genomic information is used by human cells. For example, how does the genome work to orchestrate changes in gene expression during development and differentiation? Are all genes expressed in every cell type in all human tissues? How many genes are coding or non-coding in a particular cell? What are the functions of non-coding genes? It seems clear the many answers to these questions will be found in a field of growing interest, i.e. the study of epigenetics. Epigenetic mechanisms are modifications that occur in the genetic material that do not change the nucleotide sequence, but instead may cause conformational modifications in DNA. There are basically three epigenetic modifications; DNA methylation, histone modification and regulation by non-coding RNA. This paper summarizes epigenetic regulatory mechanisms and their effects on gene transcription. Key words: Cancer; Epi-drugs; Epigenetic; Gene regulation; Histone modification; Non-coding RNAs Correspondence: T. Topal Gulhane Askeri Tip Akademisi, Fizyoloji Anabilim Dali, 06010 Etlik, Ankara, Turkey. ttopal@gata.edu.tr Received: March 4, 2011 Accepted: April 26, 2011 Published online: June 1, 2011 J Exp Integr Med 2011; 1:139-147 DOI:10.5455/jeim.060611.rw.003 Introduction DNA sequence is the same in all cells of multicellular organisms. The genome shows alternative phenotypes, which are based on different epigenetic states. Basically, this is the process by which higher organisms, especially mammals, control in a temporal and spatial manner, the expression of all genes in their genome. Epigenetic modifications of DNA, nucleosomal and chromosomal changes which collectively modify gene expression profiles and phenotypes, either increase or decrease the accessibility of several factors to the genetic material of the cells. Portions of the DNA that are transcribed can be turned on or off depending on the epigenetic modifications physically acting at that specific locus of the genome. Furthermore, it has already been demonstrated that environmental exposures, for example diet, tobacco and alcohol use, physical activity, stress, or exposure to chemical carcinogens and infectious agents influence the epigenome (the overall epigenetic state of a cell) [1-3]. These epigenetic principles and methodologies are attracting scientists from a variety of investigative fields. Historically, the word “epigenetics” (epi; on, on top of, upon) was used to describe events that could not be explained by genetic principles. The term itself was first coined by the developmental biologist Conrad H. Waddington in the 1940s, as reversible heritable changes in gene expression that occurred without alteration in the DNA sequence, but changes that were sufficiently powerful to regulate the dynamics of gene expression. Today, enormous amounts of data have been accumulated in the field of epigenetics and this field has attracted an increasing number of scientists because of its involvement not only in human physiology but also in the pathophysiology of a variety of human diseases [4]. Epigenetics, in a broad sense, is a bridge between genotype and phenotype; a phenomenon that changes the final outcome of a locus or chromosome without changing the underlying DNA sequence. Even though cells with nuclei (excluding cells such as erythrocytes) in human have the identical genotype, organismal development generates a diversity of cell types (i.e., more than 200 in the human) with disparate, yet stable, profiles of gene expression and distinct cellular functions. Additionally, most mammalian autosomal genes are expressed from both the maternally inherited and paternally inherited copies of the chromosomes. However, some genes are expressed in a parent-of- origin-specific manner. This phenomenon, known as genomic imprinting, is also regulated by epigenetic mechanisms [5]. The epigenome can be Review