Epigenetics and MicroRNAs

Abstract

Epigenetics is defined as mitotically and meiotically heritable changes in gene expression that do not involve a change in the DNA sequence. Two major areas of epigenetics-DNA methylation and histone modifications-are known to have profound effects on controlling gene expression. DNA methylation is involved in normal cellular control of expression, and aberrant hypermethylation can lead to silencing of tumor-suppressor genes in carcinogenesis. Histone modifications control the accessibility of the chromatin and transcriptional activities inside a cell. MicroRNAs (miRNAs) are small RNA molecules, ϳ22 nucleotides long that can negatively control their target gene expression posttranscriptionally. There are currently more than 460 human miRNAs known, and the total number is predicted to be much larger. Recently, the expression of miRNAs has been definitively linked to cancer development, and miRNA profiles can be used to classify human cancers. miRNAs are encoded in our genome and are generally transcribed by RNA polymerase II. Despite the growing evidence for their importance in normal physiology, little is known about the regulation of miRNA expression. In this review, we will examine the relationship between miRNAs and epigenetics. We examine the effects of miRNAs on epigenetic machinery, and the control of miRNA expression by epigenetic mechanisms. Epigenetics is defined as heritable changes in gene expression that do not involve a change in DNA sequence. (Pediatr Res 61: 24R-29R, 2007)E pigenetics is defined as heritable changes in gene expression without a change in the DNA sequence itself (1). DNA cytosine methylation and histone modifications are two important mechanisms in the area of epigenetics that have profound roles in gene regulation, development, and carcinogenesis (2-5).DNA methylation is a normal process used by mammalian cells in maintaining a normal expression pattern; it is involved in the regulation of imprinted gene expression and X-chromosome inactivation, among others (6 -8). DNA methylation occurs almost exclusively on a cytosine in a CpG dinucleotide, and is achieved by the addition of a methyl group to the 5 position of a cytosine ring mediated by DNMTs (Fig. 1). CpG sites are roughly 80% depleted in the genome, and are asymmetrically distributed into CpG poor regions and dense regions called CpG "islands" (9,10), which are often located in the promoter regions of roughly half of all the protein-coding genes. The majority of the genome is rather CpG-poor due to the mutagenicity of a methylated cytosine; a methylated cytosine can undergo spontaneous deamination to become a guanine (Fig. 2) (1, 11). CpG islands normally remain unmethylated, whereas the sporadic CpG sites in the rest of the genome are normally methylated. There is a gradual reversal of this pattern during aging that leads to sporadic methylation in the CpG islands and a global loss of methylation, but this change is particularly pronounced during carcinogenesis (Fig. 3) (1,12). Methylation of CpG islands in promo...

Viral epigenomes in human tumorigenesis

“…We now know that epigenetics, which includes the methylation status of DNA and the posttranslational modifications of histones, has an important function in tumorigenesis in mammals (Jones and Baylin, 2002;Esteller, 2008). The best-known epigenetic marker is DNA methylation, and together with specific histone modifications and specific miRNA signatures, it defines a molecular landscape that is altered in cancer (Fraga and Esteller, 2005;Chuang and Jones, 2007;Lujambio et al, 2007).…”

MicroRNAs and cancer: Profile, profile, profile

“…[68][69][70]; (ii) epigenetic regulation of miRNA expression (for details, see Refs. 71,72) and (iii) abnormalities in miRNA processing genes and proteins. We will further detail only the last mechanism.…”

TBHP-induced oxidative stress alters microRNAs expression in mouse testis

“…One of the important regulatory mechanisms at the epigenetic level is applied through microRNAs (miRNAs) [11]. MiRNAs are short (∼22 nt in length) non-coding RNA molecules that bind specifically to mRNA molecules to posttranscriptional control of gene expression [52].…”