Chromatin structure, gene regulation, and epigenomic mapping assays

Summary

Ellen Weinzapfel from EpiCypher introduces chromatin mapping basics in a video series. She explains that chromatin, made of DNA and histone proteins, regulates gene expression by controlling DNA accessibility. Closed chromatin (heterochromatin) keeps genes 'off', while open chromatin (euchromatin) allows gene activation. Histone post-translational modifications and chromatin-binding proteins play crucial roles in this process. Chromatin mapping assays, using next-generation sequencing, identify specific histone modifications and protein binding sites across the genome, which are vital for understanding disease mechanisms and drug development.

Takeaways

• 🧬 Chromatin is the biochemical structure that packages DNA inside cells, composed of DNA and histone proteins.
• 🌀 DNA wraps around histone proteins to form nucleosomes, which are the repeating subunits of chromatin.
• 🔒 Closed or inaccessible chromatin (heterochromatin) is tightly packed, while open or accessible chromatin (euchromatin) allows gene expression.
• 🛡 Alterations to chromatin structure are linked to diseases, making it a significant area in biomedical research.
• 🔑 Chromatin accessibility is crucial for gene expression; closed chromatin represses genes, while open chromatin allows gene activation.
• 🌈 Histone post-translational modifications (PTMs) and chromatin binding proteins regulate chromatin structure and gene expression.
• 🔬 Chromatin mapping assays identify the DNA wrapped around nucleosomes containing specific histone PTMs or the binding sites of chromatin-associated proteins.
• 🧬 Next-generation sequencing is used in chromatin mapping to locate PTMs and proteins across the genome.
• 💊 Chromatin regulators are defective in many diseases and are key drug targets; chromatin mapping can influence drug development.
• 📚 Chromatin mapping data is used in academic research to study disease mechanisms and develop drugs and biomarkers.

Q & A

What is chromatin and why is it important for gene expression?

Chromatin is the biochemical structure that packages approximately 2 meters of DNA inside cells, primarily composed of DNA and histone proteins. It is crucial for gene expression because it regulates the accessibility of DNA to proteins, which in turn controls whether genes are turned 'on' or 'off'.

What is the difference between heterochromatin and euchromatin?

Heterochromatin refers to tightly packed nucleosomes, which is closed or inaccessible chromatin, preventing proteins from binding and thus repressing genes. In contrast, euchromatin is characterized by nucleosomes that are farther apart, which is open or accessible chromatin, allowing proteins to bind and generally turning genes on.

How does chromatin structure relate to disease?

Alterations to chromatin structure are intrinsically linked to disease. Chromatin regulators are defective in many diseases, and understanding these alterations can help in the development of therapeutic strategies.

What are histone post-translational modifications (PTMs) and their role in chromatin structure?

Histone PTMs are chemical modifications that occur on histone proteins, typically on their tails. They come in hundreds of varieties and are crucial in maintaining distinct chromatin states. PTMs can be specific to either closed chromatin (e.g., red in the graphic) or open chromatin (e.g., green in the graphic).

How do chromatin binding proteins regulate chromatin accessibility?

Chromatin binding proteins play a role in regulating chromatin accessibility by either helping to establish or maintain closed chromatin, which keeps genes off, or by opening chromatin structure to promote gene expression.

What is chromatin mapping and why is it used in biomedical research?

Chromatin mapping is a technique used to identify the DNA wrapped around nucleosomes containing specific histone PTMs or the binding sites of chromatin-associated proteins. It is used in biomedical research to understand the mechanisms behind gene regulation and disease.

How does next-generation sequencing (NGS) contribute to chromatin mapping?

Next-generation sequencing is used in chromatin mapping assays to identify the location of PTMs and proteins across the entire genome, providing a comprehensive view of chromatin structure and its impact on gene expression.

Why is the location of chromatin-associated proteins and histone PTMs significant?

The location of chromatin-associated proteins and histone PTMs is significant because it is specifically targeted and related to the downstream impact on chromatin structure and gene expression, which can have implications for disease development and treatment.

How can chromatin mapping impact the drug development pipeline?

Chromatin mapping can influence the drug development pipeline by helping scientists study diseased versus healthy patient samples, define key chromatin mechanisms, and use this information to develop and validate drugs and biomarkers.

What are some clinical applications of chromatin mapping?

Clinical applications of chromatin mapping include identifying key drug targets in diseases where chromatin regulators are defective, as well as developing and validating therapeutic drugs and diagnostic biomarkers based on chromatin structure and function.

What is the purpose of the video series on chromatin mapping by EpiCypher?

The purpose of the video series is to educate viewers on the basics of chromatin mapping, including the fundamentals of chromatin structure, its role in gene regulation, and the techniques used to study chromatin in the context of disease.

Outlines

00:00

🧬 Chromatin Structure and Its Role in Gene Expression

Ellen Weinzapfel introduces the basics of chromatin mapping, focusing on chromatin's structure and function. Chromatin, composed of DNA and histone proteins, packages DNA into a compact form within cells. It exists in two states: closed (heterochromatin) and open (euchromatin), which regulate gene expression by controlling protein access to DNA. Closed chromatin represses gene activity, while open chromatin allows gene activation. Weinzapfel emphasizes the importance of chromatin in biomedical research due to its link with disease.

Keywords

💡Chromatin

Chromatin is the complex of DNA and proteins that make up the genetic material in the nucleus of a cell. In the video, chromatin is emphasized as the biochemical structure that packages approximately 2 meters of DNA inside cells, highlighting its crucial role in compacting DNA and regulating gene expression.

💡Nucleosome

A nucleosome is the basic unit of chromatin, consisting of a segment of DNA wound around a core of histone proteins. The script mentions that DNA wraps around histone proteins to form nucleosomes, which are the repeating subunits of chromatin, and these can be packaged tightly or loosely, affecting gene accessibility.

💡Heterochromatin

Heterochromatin refers to the tightly packed form of chromatin that is generally transcriptionally inactive. The video explains that nucleosomes can be packaged very tightly together, creating closed or inaccessible chromatin, also known as heterochromatin, which prevents gene expression.

💡Euchromatin

Euchromatin is the less tightly packed form of chromatin that is more accessible to the cellular machinery required for gene transcription. The script describes it as open or accessible chromatin, where nucleosomes are farther apart on DNA, allowing proteins to bind and generally turning genes on.

💡Gene Expression

Gene expression is the process by which information from a gene is used in the synthesis of a functional gene product, typically a protein. The video emphasizes the role of chromatin structure in regulating gene expression, with closed chromatin repressing genes and open chromatin allowing for gene activation.

💡Histone Post-Translational Modifications (PTMs)

Histone PTMs are chemical modifications to histone proteins that can alter chromatin structure and affect gene expression. The script discusses how histone PTMs, which come in hundreds of varieties, are typically located on the tails of histone proteins and are associated with maintaining distinct chromatin states.

💡Chromatin Binding Proteins

Chromatin binding proteins are proteins that interact with chromatin to regulate its structure and, consequently, gene expression. The video explains that these proteins can help establish or maintain closed chromatin or come in to open chromatin structure and promote gene expression processes.

💡Chromatin Mapping

Chromatin mapping is a technique used to identify the locations of specific histone PTMs or the binding sites of chromatin-associated proteins across the genome. The script describes how these assays use next-generation sequencing to pinpoint the location of PTMs and proteins, which is crucial for understanding their role in gene regulation.

💡Next Generation Sequencing

Next generation sequencing is a high-throughput DNA sequencing technology that allows for rapid and comprehensive analysis of genetic material. The video mentions that chromatin mapping assays use this technology to identify the location of PTMs and proteins across the entire genome.

💡Drug Development

Drug development is the process of bringing a new pharmaceutical drug to the market once a lead compound has been identified through drug discovery. The script highlights the importance of chromatin mapping in the drug development pipeline, as it can help scientists study disease mechanisms, develop and validate drugs, and create biomarkers.

💡Biomarkers

Biomarkers are biological indicators of a particular disease state or condition. The video suggests that information from chromatin mapping can be used to develop biomarkers, which are crucial for diagnosing diseases and monitoring the effectiveness of treatments.

Highlights

Chromatin is the biochemical structure that packages DNA inside cells.

DNA wraps around histone proteins to form a nucleosome, the repeating subunit of chromatin.

Nucleosomes can be packaged tightly together in closed or inaccessible chromatin, called heterochromatin.

Nucleosomes can also be farther apart in open or accessible chromatin, called euchromatin.

Chromatin structure regulates gene expression, and alterations are linked to disease.

Chromatin is a major topic in biomedical research due to its role in gene regulation.

Closed chromatin prevents proteins from binding, repressing genes or keeping them 'off'.

Accessible or open chromatin allows proteins to bind DNA, typically turning genes 'on'.

Histone post-translational modifications (PTMs) regulate chromatin structure.

PTMs are located on the tails of histone proteins and help maintain distinct chromatin states.

Chromatin binding proteins regulate accessibility by establishing or maintaining chromatin structure.

Chromatin mapping identifies DNA wrapped around nucleosomes containing specific histone PTMs or binding sites of proteins.

Next generation sequencing is used in chromatin mapping assays to locate PTMs and proteins across the genome.

Chromatin associated proteins and histone PTMs are not randomly located in the genome.

Chromatin regulators are defective in many diseases and represent key drug targets.

Chromatin mapping impacts the drug development pipeline by studying diseased versus healthy samples.

Chromatin mapping data can be used to develop and validate drugs and biomarkers.

Transcripts

Hi my name is Ellen Weinzapfel, and I am a product manager at EpiCypher.

This is the first part of our video series on the basics of chromatin mapping.

In this video, I'll review the fundamentals of chromatin structure, how it regulates gene

expression, and why we use chromatin mapping assays to study disease.

But first, let s review some basic chromatin biology.

Chromatin is the biochemical structure that packages approximately 2 meters of DNA inside

cells.

The main components are DNA and histone proteins.

DNA wraps around a set of histone proteins to form a nucleosome - the repeating subunit

of chromatin.

Nucleosomes can be packaged very tightly together, enabling more DNA to be stored in a smaller

space.

This is called closed or inaccessible chromatin, or heterochromatin.

Nucleosomes can also be farther apart on DNA, which is called open or accessible chromatin,

or euchromatin.

Chromatin structure acts to regulate gene expression, and alterations to chromatin are

intrinsically linked to disease.

As a result, chromatin is a major topic in biomedical research.

HOW exactly does chromatin  regulate gene expression?

Well this comes back to the idea of chromatin accessibility.

Closed chromatin prevents proteins from binding, and represses genes or keeps them in an "off"

state.

In contrast, accessible or open chromatin allows proteins to bind DNA, which generally

turns genes on.

So we have established the importance of chromatin accessibility to gene expression - but how

is this regulated?

What makes nucleosomes closer together vs farther apart on DNA?

There are many pathways that regulate chromatin structure.

Today we will be discussing  histone post-translational 

modifications, or PTMs, and chromatin binding

proteins.

Histone PTMs come in hundreds of varieties, and are typically located on the tails of

histone proteins.

As shown in this schematic, PTMs often associate with and help maintain distinct chromatin

states.

The red PTM in this graphic is specific for closed chromatin, while the green is localized

on open chromatin.

The next class of factors  that regulate accessibility 

are chromatin binding proteins.

There are many classes of chromatin-associated proteins, but in general you need to know

that some proteins help establish or maintain closed chromatin while others come in to open

chromatin structure or promote gene expression processes.

This brings us to the main topic of the talk: chromatin mapping.

Chromatin mapping is used to identify the DNA wrapped around nucleosomes containing

specific histone PTMs, or the binding sites of chromatin-associated proteins.

These assays use next generation sequencing to identify the location of PTMs and proteins

across the entire genome.

So, why is this important?

Chromatin associated proteins and histone PTMs are NOT randomly located in the genome.

This schematic shows genomic features that are specifically targeted by different PTMs

and proteins.

The location is related to the downstream impact on chromatin structure and gene expression.

So, going big picture - how are these data used?

And are there actual clinical applications?

It is important to note that chromatin regulators are defective in many diseases and represent

key drug targets.

Chromatin mapping can impact every step of the drug development pipeline: In the academic

setting, scientists use these tools to study diseased versus.

healthy patient samples and define key chromatin mechanisms.

This information can be used to develop and validate drugs and biomarkers.

This is the end of our first video – see our other videos for more information on the

basic steps of chromatin mapping assays!