The body is really complex. By now, you already know that - and there are so many super small parts that play big roles. So, when it comes to really understanding your body, we should break things down, dive down to those smallest molecules and elements.
Okay, so you already know that you have cells in your body - but how do they function? And what’s inside of them? There’s a lot of information to share, but in this article, our focus is on histones.
Now, you know about DNA, right? Well, you now need to think of your DNA as “blankets” that cover histones, which are actually proteins.
Understanding Histones
Our focus in this article is on histone modifications, but first - we need to talk about histones. What are they? How do they work? And why are they so important? Well, they’re actually proteins - but they are not exactly like the proteins you already know about.
See, histone proteins actually form like a spool - you know, how you have a spoon with thread around it? The thread around this spool, well, that’s your DNA. Now, there are many of these “spools” or proteins in your cell’s nucleus - and together they are called nucleosomes.
You see, the problem here is, your DNA is big - but by wrapping around this “spool” like structure, it can actually fit into your cell’s nucleus. It’s basically a way of “condensing” your DNA to make sure it fits.
Not all histones are exactly the same. You see, there are five main types that you should know about, and here they are:
- H1
- H2A
- H2B
- H3
- H4
Here’s an interesting fact - every nucleosome contains several histones, as well as about 147 DNA base pairs. And at the end of the nucleosome’s core, we can see “tails” that extend from the histones that are part of it.
But, even though there are five specific types of histones, variants can also exist. And these variants can replace the actual histones that form the nucleosome - right at the core. This can then cause many things to happen, such as change the properties of the histones or even how they function [1].
So, to sum things up - histones are proteins, they are wrapped by DNA, and they actually affect how your genes are “read” and “expressed”. That’s the basics that’ll help you better understand the rest of the article, as we’ll explore histone modification.
What is Histone Modification?
You should now have an understanding of histones - but what does it mean when they’re “modified”. Remember how we talked about the “tails” of these histones emerging from the nucleosome’s core?
Well, that’s where modifications happen. Now, when a modification happens, it's basically like a chemical reaction. It then makes changes to the histones.
There’s not just one “histone modification” that can happen - but essentially, it’s when a chemical group either gets added or removed from the histones.
Acetyl, methyl, and phosphorus are some examples of chemical groups (these are also known as amino acids) that can get added or removed.
Now, histone modification is necessary. You see, it affects gene expression and even processes that are related to your chromatin. So, let’s talk more about histone modification, how it happens, and why it’s so important.
Significance Of Histone Modification
When histone modification happens, there are different things that can follow. For example, modifications can make changes to how accessible chromatin is - or even alter the actual structure of the chromatin.
Imagine this - you’ve got multiple spools of that thread in a bucket. Now, when you stack them directly next to each other, can you see the color and texture of every single spool?
Nope! That’s because they are packed too tightly. Now, organize them more loosely, and suddenly it’s really easy to check the color of each spool.
This is actually what happens during histone modification. You see, when these chemical groups are added - it can change how tightly or loosely the histones pack against each other.
And this has an impact on how well the DNA they are wrapped around the histones can be read - similar to how you can adjust the “view” of the spool colors by arranging them differently.
Brief History Of Histone Modification Research
Researchers have come quite a long way when it comes to discoveries inside the human body - but did you know that histones were actually discovered way back in the 1880s.
Yup, that’s when Albrecht Kossel declared the term “histone” in 1884 [2], and from there, more interest was sparked in this particular area of the body.
Now, at the time, they didn’t have access to the same technology we do today, so of course, research was slow at first.
But, as technology and new methods for studying the human body came into the picture, it also became easier for researchers to look closely at histones, understand what they are, how modifications impact them, and more.
More in-depth research started at around midway through the 20th century, when researchers began to get a better understanding of things like gene regulation, epigenetics, and chromatin structure - and how they all relate to histones.
Two common histone modification processes, acetylation and methylation, were uncovered in the 1960s, and by the 2000s, researchers hypothesized a “histone code”.
Today, more research has been done, and researchers are even closing in on more accurate ways to modify certain enzymes to help our DNA, epigenetics, histone modifications, and other elements that have a big role to play in aging and disease.
Types Of Histone Modifications And Their Roles
If you recall, we talked about the fact that not all histone modifications are the same - and it’s important to know how each of the modification processes affect your genes and other functions.
Ultimately, these factors control how well your cells function - and they can be good or bad, it really depends on your epigenetics. So, in this section, we’ll share some more details about the different types of histone modifications that can happen in your body.
Acetylation
First up is acetylation - and we’re starting with this one for a simple reason. You see, before genes can be “expressed”, they first need to be “activated” - and that’s where acetylation comes in.
The main thing that acetylation does is it adds acetyl groups to the histones. Think about a time when you stretched a muscle and took a muscle relaxant. Well, turns out, the addition of acetyl to the histones causes the chromatin to “relax” similarly.
And when this happens, well, it makes it easier for proteins to “read” DNA code from the histones. That’s because they won’t be as closely packed together anymore. Remember that “activation” essentially means turning the genes “on”.
One thing that we should mention here is that acetylation can be “reversed”. You see, histone acetyltransferases (if the name’s too long, it’s also known as HATs) controls this activation process.
But when the histones need to pack up tighter against each other - well, that’s where histone deacetylases (or HDACs) come into the picture.
Methylation
Acetylation and activation - that’s a connection we can easily make by looking at what it does. Now, methylation is something that can both activate and deactivate genes. You see, during methylation, a methyl group is added to histones, instead of acetyl.
Now, one thing that we should get out of the way - there are different chemicals that can be added to this methyl group. Arginine and lysine are two examples.
When H3K4 and H3K36 methylation happens, then it’s going to activate genes. Now, on the other hand, H3K9 and H3K27 methylation does the opposite - they rather repress a gene. There’s both writers and erases here (writers add methyl groups, erases remove them).
Phosphorylation
If you recall, we talked about how these modifications happen on the tails of your histones. And that’s where phosphorylation comes in too. When phosphorylation happens, it means tyrosine, threonine, or serine gets added to these tails.
This is an area where “cell signaling” comes in. You see, when cells receive certain signals, they may trigger this process.
Now, phosphorylation is very important - you see, it plays a role in DNA repair, as well as regulating the cell cycle (that means your cell divides and dies when it should).
Apart from these, this process is also involved in gene activation, along with the other histone modifications that we’ve already covered. There are two things involved here. Histone kinases serve as the “writers’ and phosphatases serve as the “erasers”.
Ubiquitination
We also have ubiquitination, which can play a role in gene activation, but also in the elongation of transcriptions. That’s the case when lysine residues get added to H2B (a type of histone) during ubiquitination.
The lysine “residues” get added to the histones in response to signals that the cells receive. And, similar to the other ones, this process can be activated and the added lysine can also be removed. It’s ubiquitin ligases that adds them and deubiquitinases removes them.
Dimethylation
Now, one of the more complex ones - dimethylation. It’s got something to do with methylation. You see, with dimethylation, there’s a methyl group that gets added to the histone proteins too, but dimethylation actually has more specific functions.
There are, however different dimethylation processes - and they don’t all work the same.
So, let’s look at a couple of examples:
- Histone H3K4 dimethylation is linked to the activation of gene expression. It’s something that we can find at gene “promoters”. Now, this particular dimethylation process helps to recruit transcriptional activators.
- Histone H3K9 dimethylation rather has the opposite effect, repressing genes from being activated. This process helps to make the chromatin denser - and remember, when it's dense, it gets difficult for proteins to “read” your DNA.
- Histone H3R2 dimethylation is actually one of the least studied processes - especially when you compare it to the other examples we just looked at.
It seems to be involved in the regulation of genes. Plus, this dimethylation process also plays a role in the organization of your chromatin - as in, how dense or loosely those histones collect.
Histone Modifications And Gene Expression
One thing that you might’ve noticed by now is the fact that histone modifications play a role in gene expression. But, what exactly is gene expression?
Well, you know how you have genes (they’re already defined before you are even born) - now, gene expression refers to how the gene “code” is read by proteins.
And how they are “read” defines how they will affect you. At the most basic form, gene expression involves switching a gene on or off.
But that’s not all that we need to focus on here. You see, your genes might be “fixed”, but how they are “read” can be altered. And this is where epigenetics comes into the picture.
We’ll go over epigenetics a bit later, but for now, let’s focus on how modifications to histones affect how your genes are expressed.
Remember we talked about the fact that histones can pack together - either tightly or loosely. Well, this is how these histone modifications affect how your genes are expressed.
You see, the tighter they pack, the harder it is for proteins to get the “code” of your genes. And when they’re loosely packed - well, that means it’s easier to read this code.
All of this happens through the different processes that we discussed previously - acetylation, methylation, etc.
The Relationship Between Histone Modifications And Chromatin Structure
The structure of the chromatin is something that has a really important impact on your genes, as well as how well your cells function.
You see, the chromatin structure can actually affect the makeup and organization of these histones. And when that happens, it affects the availability of DNA code for proteins to “read”.
There are a few ways in which histone modifications impact the structure of the chromatin - and you have to know about all of them to really understand why it matters so much. So, let’s look closely at this relationship:
- Modifications to your histones can actually switch chromatin between either an open or close structure - and this affects how easy it is to read gene code.
It’s something that can increase availability of your genes or do the opposite. - Chromatic compaction is another term that comes up here. It’s basically something that’s affected by two things - deacetylation and methylation.
And, as the name suggestions, it tells how compact the chromatin should be packed. Once again, this translates to effects in gene expression. - Histone modifications also determine the accessibility of your chromatin - the less accessible, the fewer gene codes can be read.
Now, apart from these, histone modifications can also have an impact on the position of your nucleosome and even affect the “domain” organization inside the chromatin.
But, something really important to note here - there’s a constant interplay between the different factors that involve the chromatin.
Histone Modification Enzymes
Take a moment to think about this situation - you’re tasked to write an essay for class, or perhaps even a paper or craft a document for an upcoming meeting.
There are a few people involved in this process. You’re the writer, but what about the process of reviewing and editing? Well, that’s where an eraser comes in, removing content that doesn’t really fit. And then there’s the reader - who won’t make any edits, but rather just read and assess.
There’s some similarities between this situations and histone modification enzymes. You see, there are writers, erasers, and readers, so let’s take a look at each of them [3].
Writers: Enzymes That Add Modifications
The writers are, just as you would imagine, the enzymes that “write” modifications into your histones. There are enzymes that have the ability to add certain molecules, residue, or sometimes groups of chemicals onto the “tails” of your histones.
There are a couple of these, so knowing about each can be helpful. Let’s take a closer look:
- Histone Acetyltransferases (HATs) adds acetyl to the lysine residues that are present on the histones. This is how histone acetylation happens.
- Histone Methyltransferases (HMTs) add entire methyl groups to the lysine on your histones. They can also add these groups to arginine. The result: histone methylation.
- Histone Phosphorylases are kinases that have the ability to add phosphate groups to a number of amino acids, like tyrosine, threonine, and serine.
- Histone Ubiquitin Ligases are enzymes that add ubiquitin molecules to your histones. This results in ubiquitination.
Erasers: Enzymes That Remove Modifications
Erasers, on the other hand, are capable of actually removing the “modifications” that writers make to your histones. This actually “reverses” the modifications and can restore the histone to a previous state.
Here’s a quick look at the main enzymes that are erasers:
- Histone Deacetylases (HDACs) are the enzymes that remove acetyl from the lysine residues on your histones [4].
- Histone Demethylases (HDMs) removes methyl groups that happen before histone methylation activates.
- Histone phosphatases are also able to remove phosphate groups that were added to your histones.
- Histone Deubiquitinases (DUBs) are able to remove the ubiquitin molecules that the writers added to the histones.
Readers: Proteins That Recognize Modifications
Readers have a “read-only” access to your histones. They can read what was written and won’t see what was erased. These readers can then take action based on what they “read”. There are four main ones:
- Bromodomain-containing Proteins
- Chromodomains
- Tudor Domain-containing Proteins
- Plant Homeodomain (PHD) Finger Proteins
Role Of Histone Modification In Development And Disease
We’ve established the important role of histone modifications - but how does it affect development and disease?
You see, when histone modification works properly, it helps cells develop and grow, and then divide properly. It’s something that’s important for every cell that you have in your body - including your stem cells.
In your stem cells, histone modifications happen to ensure these cells can differentiate. You should already know that not every cell in your body is the same. Some cells play a role in your heart, others in your brain, others in your pancreas, etc.
So, being able to differentiate and become specialized cells is important - and even then histone modifications still help these cells function as they should.
Now, sometimes, histone modifications don't happen like they need to - and when there are “bad” reactions, it can lead to disease.
In people with cancer, it’s often found that histone acetylation and methylation doesn’t happen like they should [5].
Other histone modification types can also weaken - and this can cause problems like poor DNA repair or even inappropriate shut down of genes that helps to suppress tumors.
Factors That Influence Histone Modification
Okay, so you can inherit some problems with histone modification that’s basically set in your genes, but did you know that your own life (such as lifestyle habits and exposures) also contributes? Well, let’s see what factors have the biggest influence:
Diet: Start with the food you eat. If you don’t like to eat your veggies and enjoy takeaway burgers every second night of the week, well - that’s something that will adversely affect histone modification.
A healthy diet, however, that’s low in saturated fats and sugars, can help to improve these processes.
Stress: While we all have to deal with stress sometimes, there are those with chronic stress. And this means you are constantly flooded with cortisol and other stress hormones - which creates inflammation, increases oxidative stress, and damages histone processes.
Pollution: What you are exposed to in the environment also affects histone modification, such as harmful toxins and air pollutants.
Ethical Implications Of Histone Modification
If you look at research, one thing is for sure - there are a lot of advancements and discoveries that researchers have made in the last few years.
Some of these include making modifications to things like epigenetics and histone modification. But, there are ethical implications that come to mind here.
For example, the long term complications are not clear, and this creates the opportunity for unintended consequences.
Manipulating your epigenome is also considered a possible hazard - something that could cause problems when researchers are not absolutely sure how everything they do will affect you.
Other ethical considerations include informed consent, as well as the patient’s privacy. Plus, there’s the question of access. Will only the rich get access to these solutions that could save lives potentially?
Or will they become available to all? These are things that need to be discussed, researched, and addressed for histone modification procedures, along with other gene-related therapies, to become a more “ethically acceptable” option.
Frequently Asked Questions
What is the function of histone modifications?
Think about wrapping a couple of items in blankets - and every blanket has a pattern on it. Now, hold them close together.
Can you see the pictures on the sides of the blankets? It’s going to be hard! Histones are proteins with DNA folded around them, but like those blankets. They say what parts of DNA can be read.
What are the 3 most common histone modifications?
Now, there are a couple of histone modifications. But, when it comes to the most common ones - those would be acetylation, methylation, and phosphorylation.
They each play their own role in helping to make sure your body works, cells divide, and functions don’t go awry.
How do histone modifications affect gene expression?
They pack together loosely or tightly - and that determines which genes from your DNA cells can read. Okay, it’s a little more complex than this.
There’s the chromatin structure, the transcription factor binding, and the chromatic modifier recruitment - three processes that happen when your genes are expressed.
Why do histone modifications matter?
Just think what would happen if every program on your computer launches as you start the device up.
Well, that’s surely going to be a problem. Similarly, every cell doesn’t need every gene in your DNA makeup when it performs a function. So histone modifications help to avoid this from happening.
What is affected by modifications in histone proteins?
As modifications happen to your histone proteins, there are some things in your body that get affected in the process.
One particularly important “thing” that gets affected is gene expression. But modifications to your histones can also affect your development, disease, and how your cells function.
How does histones control gene expression?
They go through modification processes. And when this happens, they “reorganize” themselves - and that makes sure that only the right genes are expressed when proteins read your genetic code.
But modifications can also be “bad” and cause the switch on the wrong genes to be flipped!
Can histone modifications be inherited?
It’s actually related to epigenetic inheritance. Need a short answer? Yes! You can inherit histone modifications, but it doesn’t mean you are definitely going to develop a disease or another hereditary problem.
So, don’t just rely on whether you’ve inherited gene modifications that affect your histones.
Can histone modifications be reversed?
Naturally, yes. You see, there are enzymes that can actually remove histone modifications. But when histone modifications are “bad”, additional therapies may be needed to make the removal more effective.
Of course, there’s still a lot of ongoing research on how human intervention (through lifestyle changes and pharmaceutical approaches) could help.
Conclusion
Histones are proteins and sure, they’re incredibly small, but wow - they play such a big role in keeping your cells functioning. In fact, some histone modifications can predispose you to serious diseases.
That’s quite unfortunate, but there are things that you can do. What do you prefer to eat during the day? And how many calories are in those foods? What about smoking, drinking, and how much sleep do you get?
You see, all of these play a really important role in preventing those “bad” histone modifications and promoting better functionality of these tiny proteins. Start with the guidance we looked at in this article, then take things from there.
References
- Histones: The critical players in innate immunity. Retrieved from https://pubmed.ncbi.nlm.nih.gov/36479112/
- Histone. Retrieved from https://www.chemeurope.com/en/encyclopedia/Histone.html
- Histone modifying enzymes: structures, mechanisms, and specifities. Retrieved from https://pubmed.ncbi.nlm.nih.gov/18722564/
- Erasers of histone acetylation: the histone deacetylase enzymes. Retrieved from https://pubmed.ncbi.nlm.nih.gov/24691964/
- Histone Modifications and Cancer. Retrieved from https://pubmed.ncbi.nlm.nih.gov/27037415/
