15 Epigenetics

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We have seen how neurotransmitter action can alter gene transcription and translation through binding to G-protein coupled receptors. The effectiveness of the signaling cascade on new protein synthesis does depend on some DNA-specific factors. This chapter will briefly cover how genes are transcribed and then how non-sequence, molecular changes to DNA can affect transcription rates.

Central Dogma

DNA to RNA to protein. The central dogma of genetics. It may look simple, but many complex steps must occur for the process to be successful.

DNA

Doubled-stranded DNA (deoxyribonucleic acid) is comprised of four nucleotide bases: adenosine (A), thymine (T), guanine (G), and cytosine (C). Adenosine and thymine form base pairs whereas guanine and cytosine form pairs. The pairs cause the two strands to coil around each other and form a double helix.

RNA

The single-stranded messenger RNA (ribonucleic acid) is created from the DNA sequence via complementary base pairing. Like DNA, there are four bases, but in RNA the thymine base is replaced by uracil (U). Messenger RNA (mRNA) leaves the nucleus and interacts with ribosomes to synthesize proteins in a process called translation. The ribosomes pair amino acids to specific three-base sequences called codons. For example, the codon sequence AUG is the start codon and it codes for methionine. The ribosomes will move down the mRNA to find the start codon of the protein and begin translation there, adding a new amino acid for each codon until a stop codon is reached.

Protein

Proteins are synthesized by the linking of amino acids together by the ribosomes. There are 20 amino acids that are each encoded by one or more mRNA codon sequences.

A diagram showing the central dogma: DNA (double helix with base pairs A-T, C-G) undergoes transcription in the nucleus to produce mRNA (single strand with U replacing T), which undergoes translation at ribosomes to produce proteins (chains of amino acids). Link to detailed alternative text in caption.
Figure 15.2. Central dogma of molecular biology. In the nucleus, DNA (composed of nucleotides A, T, C, G) is transcribed into mRNA (A, U, C, G—where uracil replaces thymine). At ribosomes, mRNA is translated into proteins composed of amino acid chains. Each three-nucleotide codon specifies one amino acid, establishing the genetic code that directs protein synthesis. ‘Central Dogma’ by Casey L. Henley (CC-BY-NC-SA). View detailed alternative text.

Gene Transcription

In the nucleus, proteins called transcription factors and an RNA polymerase attach to the DNA. The DNA unwinds, the proteins bind, and an mRNA strand is synthesized using the DNA as a template. The mRNA is a complementary sequence to the DNA strand being transcribed.

A diagram showing transcription where RNA polymerase and transcription factors bind to unwound DNA, with RNA polymerase synthesizing an mRNA strand complementary to the DNA template strand. Link to detailed alternative text in caption.
Figure 15.2. Transcription machinery. The DNA double helix unwinds, creating a transcription bubble where transcription factors and RNA polymerase bind. RNA polymerase reads the DNA template strand and synthesizes a complementary mRNA strand through base pairing (A pairs with U, T pairs with A, C pairs with G, G pairs with C). This process converts genetic information from DNA into RNA. ‘Transcription’ by Casey L. Henley (CC-BY-NC-SA). View detailed alternative text.

DNA must be unwound from its condensed form to allow for gene transcription

DNA Packaging

DNA is not always accessible to those transcription proteins, though. There is so much DNA in each cell, that in order to save space, it is highly condensed in the nucleus. The double helix is wrapped around proteins called histones. The histones are then wrapped into nucleosome strands. The nucleosomes are compacted into denser structures called chromatin. Finally, the chromatin is condensed more and creates chromosomes.

A diagram showing DNA packaging stages from double helix to chromosome: DNA wraps around histones forming nucleosomes, which compact into chromatin fibers, which further condense into the final chromosome structure, achieving massive size reduction. Link to detailed alternative text in caption.
Figure 15.3. Hierarchical DNA packaging. To fit approximately 2 meters of DNA into the microscopic nucleus, DNA wraps around histone octamers forming nucleosomes (beads-on-a-string structure). Nucleosomes compact into chromatin fibers, which undergo further folding and condensation to form chromosomes visible during cell division. This packaging must be reversible to allow gene transcription. ‘DNA Packaging’ by Casey L. Henley (CC-BY-NC-SA). View detailed alternative text.

In order for gene transcription to occur, the strands of DNA must uncoil from the histone bodies to become accessible to the transcriptional machinery.

A diagram comparing tightly wound chromatin (where RNA polymerase cannot access DNA, preventing transcription) with loosely wound chromatin (where unwound DNA allows RNA polymerase binding and active gene transcription), connected by reversible unwinding/re-winding. Link to detailed alternative text in caption.
Figure 15.4. Chromatin accessibility regulates transcription. Tightly wound DNA around histones blocks transcription factor and RNA polymerase access, silencing genes. Chromatin remodeling unwinds nucleosomes, exposing DNA for protein binding and enabling transcription. This reversible process allows dynamic control of gene expression in response to cellular signals, including those from neurotransmitter pathways. ‘RNA Polymerase Binding’ by Casey L. Henley (CC-BY-NC-SA). View detailed alternative text.

Molecular modifications to the DNA (the epigenome) can alter the ability for gene transcription

Epigenetics

Molecules such as methyl groups can be attached to DNA or on the histones. These epigenetic tags can affect how tightly the DNA is wound around the histones. Since gene expression can be altered by modifying how easily the histones unwind and how accessible DNA strands are, epigenetic tags are able to have an indirect effect on gene transcription.

Methyl groups make it more difficult for the polymerase to access the DNA by keeping the DNA coiled around the histones, reducing transcription. When the methyl groups are removed, called demethylation (not to be confused with dimethylation, the addition of two methyl groups), gene expression can increase because the DNA uncoils and is accessible to the transcriptional machinery.

A diagram showing how DNA methylation regulates transcription: high methylation keeps chromatin tightly wound and inaccessible (blocking transcription), while demethylation loosens chromatin, allowing RNA polymerase binding and gene transcription, with reversible methylation/demethylation cycles. Link to detailed alternative text in caption.
Figure 15.5. DNA methylation as an epigenetic regulator. Methyl groups attached to cytosine bases affect chromatin structure without altering DNA sequence. High methylation maintains tight DNA-histone association, blocking transcription factor and RNA polymerase access and silencing genes. Demethylation loosens chromatin, enabling transcription. Methylation patterns can be modified by life experiences and cellular signals, providing a mechanism for environment-responsive gene regulation. ‘DNA Methylation’ by Casey L. Henley (CC-BY-NC-SA). View detailed alternative text.

Epigenome is Flexible

An individual’s DNA sequence is fixed (excluding mutations that occur due to damage or errors in cell replication), but the epigenome is flexible and can change throughout life. An individual’s life experiences, especially during development or other critical periods, are able to alter the epigenome.

Some experiences will increase methylation, sometimes for only certain genes, sometimes genome-wide, whereas other experiences will decrease it. For example, early life stress can increase the amount of methylation found on the gene that encodes for the receptor that is activated by stress hormones. Increased methylation leads to reduced transcription which has downstream effects on the negative feedback loop on the stress response. Scientists are starting to realize how important the epigenome is in regulating our brain and behavior.

Inherited Epigenome

The inheritance of epigenetic modifications is an active area of research with some fascinating but complex findings. Unlike DNA mutations, which are clearly passed from parent to offspring, epigenetic inheritance is much more complicated and still being studied. Some research suggests that certain epigenetic modifications can be passed from parents to their children, and in some cases even to grandchildren. However, this type of inheritance is not as straightforward as traditional genetic inheritance.

There are several important limitations to epigenetic inheritance. During the development of egg and sperm cells, most epigenetic markers are erased in a process called reprogramming, making it difficult for epigenetic changes to be inherited by the offspring. Also, while both parents can potentially pass on epigenetic changes, the mechanisms are still not well understood. In humans, the study of transgenerational epigenetic inheritance is particularly complex. Separating the effects of shared genetics and environment from true epigenetic inheritance is particularly difficult in humans.

A family pedigree diagram showing transgenerational epigenetic inheritance where a stressed grandparent develops DNA methylation that is transmitted to children (F1) and grandchildren (F2), demonstrating that environmental effects can be inherited across generations through epigenetic modifications. Link to detailed alternative text in caption.
Figure 15.6. Transgenerational epigenetic inheritance. Environmental stress experienced by a grandparent can induce DNA methylation patterns that are transmitted to F1 (children) and F2 (grandchildren) generations, even without direct exposure to the original stressor. This demonstrates how life experiences can affect descendants through inherited epigenetic modifications. However, such inheritance is complex, involving germline transmission, and most methylation marks are erased during reproductive cell development, making this phenomenon less common than traditional genetic inheritance. ‘Transgenerational Methylation’ by Casey L. Henley (CC-BY-NC-SA). View detailed alternative text.

Conclusion

Epigenetic modifications provide a flexible mechanism for regulating gene expression without altering the underlying DNA sequence. These modifications, influenced by life experiences and environmental factors, can have lasting effects on neural function and may even be passed to future generations. Understanding epigenetics helps explain how the brain adapts to experiences and how environmental factors can influence neural development and behavior.

Key Takeaways

  • DNA is highly condensed in the nucleus
  • The DNA must unwind for transcription to take place
  • Epigenetic modifications can alter how easily the DNA can unwind
  • Epigenetic modifications can be inherited

Important Terminology

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Foundations of Neuroscience Copyright © 2021 by Casey Henley is licensed under a Creative Commons Attribution-NonCommercial-ShareAlike 4.0 International License, except where otherwise noted.

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