#histone modifications

Hello, hello! Today's topic is histone modifications. We are continuing on with the epigenetics theme after my previous educational post about DNA methylation. As described in that post, epigenetics is the study of heritable genetic modifications without a change in DNA sequence (Takuno & Gaut, 2012). Similarly to DNA methylation, histone modifications affect gene expression through regulation of accessibility of the DNA for transcription (Bartova et al, 2008). But before we get into these modifications, let's go over a bit of background information!

What is a histone, anyway? A histone is a type of protein involved in DNA compaction and organization. In order to fit a genome's worth of DNA into the nucleus of a cell, that stuff needs to be extremely tightly packed! Histones help with this by forming an octomer called a nucleosome, which the DNA wraps around. These nucleosomes then coil together to form a fiber known as chromatin, which goes on to make up a chromosome. When the chromatin is less tightly packed, it is known as euchromatin and it is available for transcription (Bartova et al, 2008). When it is more tightly packed, it is known as heterchromatin, and polymerase proteins cannot access and transcribe the DNA (Bartova et al, 2008). Histone modifications regulate the transition between heterochromatin and euchromatin (Bartova et al, 2008).

(Above image from humanoriginproject.com)

(Above image from Caputi et al, 2017)

The octomer core of a nucleosome is made up of two copies of each of four types of histones: H2A, H2B, H3, and H4 (Marino-Ramirez et al, 2017). Each of these histones includes an N-terminal tail structure, which is the main site of modification (Marino-Ramirez et al, 2017). The tails are modified through addition and removal of certain functional groups or other small structures. Types of modifications include acetylation by histone acetyltransferases, methylation by histone methyltransferases, phosphorylation by kinases, and ubiquitination (Marino-Ramirez et al, 2017). All of this information is used for naming specific histone modifications: Which histone is modified, which amino acid of the histone tail the modification is on, what type of modification is made, and in what amount. For example, H3K9me2 is the name for di-methylation of the 9th Lysine on an H3 histone's tail.

Some important histone modifications and their effects include:

H3K9me2: transcriptional activation + maintenance of CHG DNA methylation in plants

H3K9me3: transcriptional repression

H3K9ac: transcriptional activation

H3K4me1 & H3K4me3: transcriptional activation

H3K27me3: transcriptional repression

H4K16ac: transcriptional activation

H3S10p: DNA replication-related chromatin condensation

(He & Lehming, 2003)

Epigenetics is a fast-growing field that truly goes “above and beyond” genetics as its name suggests. This field of research involves studying the changes in gene expression that do not result from changes in the sequence of DNA. It is fascinating to discover that there is much more to our DNA than the astonishing 3 billion base pairs packed into each one of our cells. A strand of DNA does not exist alone in the nucleus but is wrapped around protein octamers known as histones. These units, called nucleosomes, are wound into increasingly organized structures. From here, it only gets more complicated because this organization is dynamic. DNA and histones can be chemically modified in several ways that initiate changes in structure and thus changes in expression of specific genes. For instance, DNA methylation of cytosine nucleotides is known to cause the silencing of a gene. This is accomplished directly when the methyl group blocks a transcription factor from binding to a promoter or indirectly when the methylation recruits cellular machinery that induces gene silencing histone modifications. Histone modifications are the other route of epigenetic control of gene expression, which involves the addition of chemical groups to lysine residues of histone proteins. This alters the structure of the chromatin and changes the availability of regulatory DNA to be accessed by transcription machinery. There are dozens of histone modifications that comprise a code that changes patterns of gene expression. One well-known example is histone acetylation which increases gene expression by causing DNA to be less tightly wound around histones and thus more accessible for transcription. Researchers are only beginning to elucidate the epigenetic changes at the DNA and histone modification levels that control gene expression.

Epigenetic modifications are implicated in the many different areas of neuroscience. They are dynamic and vulnerable to disruption and represent the intersection of our genes and the environment. For example, epigenetic changes are known to play a role in psychiatric disorders such as schizophrenia. Epigenetic changes can occur throughout life but are thought to be especially important during the early phases of development. DNA methylation and histone modifications are implicated in several other neurobiological processes, such as learning and memory. These processes involve long term changes in the brain in response to environmental cues, so it is plausible that changes in gene expression due to epigenetic changes may be implicated. Epigenetic changes during memory formation may be influenced by the activity of CREB. CREB is a transcription factor that is implicated in memory formation. Knockout of this cAMP response element-binding protein in mice causes them to display learning and memory deficits. It is hypothesized that contextual fear conditioning and the resulting long term potentiation cause changes in CREB which then alters gene expression by altering epigenetic marks.

Several types of epigenetic changes have been observed in animal models of learning and memory. For instance, it has been demonstrated that there is an increase in DNA methylation after behavioral fear conditioning, which suggests that learning causes silencing of DNA (Molfese, 2011). This illustrates the counterintuitive notion that learning involves the suppression of genes that were active in addition to activating genes that were suppressed. One theory based on this research is that certain genes may be actively suppressing memory formation until learning is needed. When a context arises where learning would prove beneficial, these genes are turned off via methylation (Molfese, 2011).

Other studies have examined histone modifications in relation to learning and memory and reported significant findings indicating that this category of epigenetic changes is important for long term memories as well. For instance, pairing a shock with short exposure to a new context causes one type of histone acetylation while a longer exposure to the context followed by a shock causes acetylation of a different histone (Molfese, 2011). These results indicate that different types of learning are due to different types of epigenetic changes. Additionally, the acetylations observed in these experiments lasted only briefly, just 1-2 hours. However, the researchers noted that certain chemicals can prolong this acetylation. Finally, histone methylation is also thought to play a role in memory formation. Patterns of histone methylation in area CA1 of the rat hippocampus are altered following contextual fear conditioning and other memory tasks (Molfese, 2011). Interestingly, mice that lack specific methyltransferases show deficits in memory, which supports the importance of these modifications in the formation of memories.

This field of research strongly suggests that a variety of epigenetic alterations are important for the formation of memories. Alterations that cause deficits in the brain’s ability to institute these modifications following an event impair the ability to form memories. Additionally, it was demonstrated that certain molecules can enhance memory acquisition. Research on the contribution of epigenetic modifications in the context of memory formation is a growing field that can have important implications in understanding memory consolidation and the failure of the system to work properly. The implications of this research could be significant in that it could lead to therapies for those with disorders that cause disruption in memory formation as well as treatment for healthy individuals to bolster memory performance. 

References:

Scientists have mapped how healthy gut tissue uses chemical switches to prevent stem cells from becoming cancerous. Intestinal stem cells normally reside in a specialized environment that keeps them in a youthful, flexible state through activating chemical tags on DNA called H3K27ac. When these cells migrate away to form specialized gut lining, they accumulate opposing repressive tags called H3K27me3 that lock away stem cell programs. This epigenetic balancing act acts as a gatekeeper, ensuring adult cells do not reactivate fetal growth patterns. Cancer appears to disrupt this system by removing the repressive marks, allowing mature cells to revert to stem-like states and replenish tumors. These findings suggest that restoring these chemical locks could offer new ways to stop colorectal cancers from recurring after treatment.

In a study published in Environmental Toxicology and Pharmacology, scientists set out to learn more about the epigenetic effects of excessive fluoride exposure. In particular, they focused on the role of histone modification in the development of skeletal fluorosis, a crippling and painful bone disease that affects millions of people worldwide.