Epigenetics, Chromatin Structure, and Gene Regulation

Epigenetics and Chromatin Structure

Introduction to Epigenetics

Epigenetics refers to heritable changes in gene expression that do not involve alterations to the underlying DNA sequence. These changes can affect how genes are turned on or off and are crucial for development, cellular differentiation, and response to environmental factors.

• Epigenetic phenomena include DNA methylation, histone modification, and chromatin remodeling.

• Cloning experiments (e.g., nuclear transplantation in cows and cats) demonstrate that genetically identical organisms can have different phenotypes due to epigenetic differences.

• Example: "Copy Cat" is a clone of "Rainbow"; both have identical DNA but different phenotypes due to epigenetic variation.

DNA Methylation

DNA methylation is a key epigenetic modification where a methyl group is added to the cytosine base in a CpG dinucleotide by DNA methyltransferases (DNMTs).

• Methylation patterns are copied during DNA replication, allowing for heritable gene regulation.

• Heavily methylated DNA is typically associated with repression of transcription.

• DNA methylation at CpG islands (regions rich in CpG sites) can silence gene expression by preventing transcription factor binding or recruiting proteins that compact chromatin.

Equation:

$\text{Cytosine} + \text{Methyl group} \xrightarrow{DNMT} 5\text{-methylcytosine}$

Chromatin Structure: Euchromatin vs. Heterochromatin

Chromatin is the complex of DNA and proteins (mainly histones) that packages genetic material in the nucleus.

• Euchromatin: Relaxed, lightly stained regions; transcriptionally active.

• Heterochromatin: Highly condensed, darkly stained regions; transcriptionally inactive (genes are silenced).

• Chromatin is roughly 1/3 DNA, 1/3 histones, and 1/3 nonhistone proteins, with significant RNA content.

• Histones are positively charged and bind tightly to negatively charged DNA.

Histone Modifications

Histone tails can be chemically modified by enzymes, affecting chromatin structure and gene expression.

• Acetylation: Addition of acetyl groups to histone tails leads to euchromatin formation and active transcription.

• Methylation: Addition of methyl groups can lead to either heterochromatin or euchromatin, depending on the specific amino acid modified.

Chromatin Remodeling and Gene Expression

Transcription requires changes in chromatin structure to expose gene promoters.

• Transcription factors bind to enhancers and recruit chromatin remodeling proteins.

• Promoters are exposed by removing or repositioning nucleosomes.

• DNase sensitivity assays can distinguish between euchromatin (short fragments, accessible) and heterochromatin (long fragments, inaccessible).

Epigenetic Inheritance

Epigenetic marks can be inherited across generations, but the mechanism depends on whether the exposure is intergenerational or transgenerational.

• Intergenerational inheritance: Both the F1 and its germ line (future F2) are exposed to the environmental trigger.

• Transgenerational inheritance: Only observed if the trait persists in generations not directly exposed to the trigger (e.g., F3 in maternal exposure).

Genomic Imprinting

Genomic imprinting is the differential expression of genetic traits depending on the parent of origin, often regulated by DNA methylation.

• Imprinted genes are silenced by methylation, so only one parental allele is expressed.

• Example: The Igf2 gene in mice is only expressed from the paternal chromosome; loss of function in the paternal allele leads to small offspring, while loss in the maternal allele has no effect.

• Imprints are reset during gamete formation and established according to the sex of the parent.

Comparison of Genetic and Epigenetic Changes

	Genetic Change	Epigenetic Change
Caused by nucleotide sequence change	✔️
Caused by change in DNA packaging		✔️
Irreversible	✔️
Reversible		✔️
Can cause disease	✔️	✔️
Changes which DNA sequences are read		✔️

Control of Gene Expression

Gene expression is regulated at multiple levels, including chromatin structure, DNA methylation, histone modification, and environmental factors. These mechanisms ensure that genes are expressed only when needed and in the appropriate cell types.

• Environmental exposures, habits, and other factors can influence epigenetic marks and gene expression.

Additional info:

• Epigenetic changes are reversible and can be influenced by environmental factors, making them a key area of study in development, disease, and inheritance.