Histone deacetylase 5

Transcription

So, the regulation of gene expression can be modulated at virtually any step in the process, from the initiation of transcription all the way to post-translational modification of a protein, and every step in between. And it's the ability to regulate all these different steps that helps the cell to have the versatility and the adaptability of an efficient ninja, so that it expends energy to express the appropriate proteins only when needed. Or, you can think of the cell as a lazy couch potato that wants to expend the least amount of energy as possible. So, starting at the beginning of gene expression, let's talk about gene regulation as it pertains to DNA and chromatin regulation. Let's talk about the structure of DNA. DNA is packed into chromosomes in the form of chromatin, also know as supercoiled DNA. And so, chromatin is made up of DNA, histone proteins, and non-histone proteins. And there are repeating units in chromatin, called nucleosomes, which are made up of 146 base pairs of double helical DNA that is wrapped around a core of eight histones. And there are four different types of histones within this structure of eight that you should be aware of. And they're named H2A, H2B, H3, and H4, that's just the nomenclature they've been given. Now, acetylation occurs at the amino terminal tails of these histone proteins by an enzyme called histone acetyltransferase, which I'll just abbreviate as HAT. And this is a reversible modification, so the acetylation of histones is sort of kept in balance by another enzyme that removes these acetyl groups, which is called histone deacetylase, or HDAC. The acetylation of histones leads to uncoiling of this chromatin structure, and this allows it be accessed by transcriptional machinery for the expression of genes. On the flip side of this, histone deacetylation leads to a condensed, or closed structure of the chromatin, and less transcription of those genes. When these modifications that regulate gene expression are inheritable, they are referred to as epigenetic regulation. So, when it comes to gene expression and DNA, you can basically think of DNA as coming in two flavors, densely packed, and transcriptionally inactive DNA, which is called heterochromatin, and then less dense, transcriptionally active DNA, which is euchromatin. And I like to think of heterochromatin as being densely packed and hibernating, like heterochromatin and hibernating both begin with H, kind of like a bunch of densely packed bears that are closed off in their cave for the winter, whereas euchromatin is waiting there with open arms, welcoming the transcriptional machinery to transcribe away. Now often you will see that histone deacetylation is combined with another type of DNA regulatory mechanism, and that is DNA methylation, and this occurs in a process called gene silencing. And this is a more permanent method of sort of down-regulating the transcription of genes. And DNA methylation involves the addition of a methyl group, which is a carbon with three hydrogens, to the cytosine, DNA nucleotides, by an enzyme appropriately called methyltransferase. And this typically occurs in cytosine-rich sequences called CpG islands. Don't forget that cytosine pairs with g, guanine, so that's why they're cg islands that you'll find. DNA methylation stably alters the expression of genes, and so it occurs as cells divide and differentiate from embryonic stem cells into specific tissues. And so this is essential for normal development, and is associated with other processes, such as genomic imprinting, and x-chromosome inactivation, topics for another discussion. And abnormal DNA methylation has been implicated in carcinogenesis, or the development of cancer, so you can see how the normal functioning of DNA methylation is a critical regulatory mechanism for our cells. Now, DNA methylation may effect the transcription of genes in two ways. First, the methylation of DNA itself may physically impede the binding of transcriptional proteins to the gene. And second, and likely more important, methylated DNA may be bound by proteins known as methyl cpg-binding domain proteins, or MBDs, for short. Now MBD proteins can then recruit additional proteins to the locus, or particular location in a chromosome, certain genes, such as histone deacetylases, and other chromatin remodeling proteins, and this modifies the histones, forming condensed, inactive heterochromatin that is basically transcriptionally silent.