[MUSIC] Hello, my name is Lena Smirnova. And I am research associate here in Johns Hopkins. And today's lecture will be focused on epigenetics and microRNAs. And they are all in toxicology and environmental health. Why I am interested in microRNAs? I started to work with them since I was PhD student back in 2002, when micro RNAs were discovered and their research started in this area. The first session of this lecture will be on epigenetics. So what is epigenetics? Epigenetics is the mechanisms of gene regulation without changing the DNA sequence that can be stable inherited through mitosis. If you imagine the computer, our genome will be the hardware and the epigenenome would be software. Our genetic information is packed in chromosomes. Each chromosome consists of chromatin. Chromatin is a chain of nucleosomes. Every single nucleosome contains from proteins called histones, which packed in the octamer structure. And DNA helix wound around those histones. Chromatin structure is regulated by two major epigenetic mechanisims, DNA methylation and and post-translational histone modification. DNA methylation is an addition of methyl group CH3, as you can see here in the red circle, at cytosine residues. Which is often, but not exclusively, packed in these CpG islands. The enzyme responsible for the methylation of DNA, called DNA methyltransferases, there are three forms of this enzyme. And DNA methyltransferase 1 is responsible for maintenance of established patterns of DNA methylation following DNA replication. And DNA methyltransferase 3A and 3B are responsible for de novo methylation. So the main functions of DNA methylation is to regulate gene expression, transposon silencing, embryonic development, genomic imprinting, and X-chromosome inactivation. For example, usually DNA is methylated in promoter regions. And if promoter region of the gene is unmethylated, it's mean it's active. So the transcription factors and RNA polymerase can bind to the promoter and initiate transcription. However, if the promoter is methylated, the transcription factors cannot bind to the promoter. And gene is silenced. The second mechanism, as I mentioned before, is histone modifications. There are several types of histone modifications, which is acetylation, methylation. Phosphorylation, ubiquitination, and bionylation. And there are several enzymes, as writer and erasers, to regulate this process. To add acetly or a methyl group to the histone acetlytransferase and methyltransferase are involved. And to erase those groups, histone deacetylase and histone demythilase are involved. Protein kinase and phosphatase are regulate the phosphorylation of the histones. This table shows you the different histone marks, acetlyated or methylated. Usually histone 3 and 4 are regulated by methylation acetylation. And usually this is lysine residues which marks are the key. This histone mechanism, DNA methylation, and histone modification regulation expression by changing the chromatin structure. DNA methylation and methylation of certain lysin residues in histones make chromatin more condensed, thus prevent gene expression, as you can see in the upper-right corner. In this chromatin state called heterochromatin, demethylation of DNA and acetlylation of histone make chromatin less packed, more open, for transcription machinery and this state of chromatin called euchromatin. In this stage I introduced you to the epigenetics and the mirror mechanism of epigenetics. In the next section we will talk about epigenetics and environment.
