Understanding the Epigenome

Environmental Influences on the Epigenome

• Environmental factors influence gene expression without altering the primary DNA sequence.
• This process allows for immediate adaptation to the environment.
• Key epigenetic regulators include histone modifications, DNA methylation, and non-coding RNA expression.

Outline

• How to modify protein expression after translation: Process of altering protein function after its initial synthesis.
• What is Epigenetics?: Study of heritable changes in gene function not linked to the DNA sequence.
• How can epigenetics be influenced by environmental factors?: Impact of the environment on gene expression.
• Current research status and future directions: State of knowledge on the subject.

Introduction

• The epigenome influences gene expression and subsequent protein expression.
• Epigenetic regulation allows immediate organism-level adaptation to the environment.
• Three major epigenetic regulators: histone modifications, DNA methylation, and non-coding RNA expression.

How can change be introduced at the post-translation level?

• Proteins vary substantially from genes.
• Protein modifications (post-translation) include methylation, acetylation, phosphorylation, and glycosylation.
• These modifications impact protein: folding, stability, localization, function, activation, and interactions.

The diversity and complexity of proteins

• Post-translational modifications are chemical modifications playing key roles in functional proteomics.
• These modifications influence protein activity, localization, and interactions with other cellular molecules.

PTMs increase proteome diversity

• Human genome has 21,000-22,000 genes.
• The human proteome comprises over 1 million proteins.
• Single genes can encode multiple proteins through genomic recombination, alternative promoters, differential transcription termination, and alternative splicing.
• Post-translational modifications (PTMs) increase the complexity of the proteome from the genome level.

Epigenetics

• Epigenetics is the study of heritable changes in gene function not directly linked to the DNA sequence.
• Such changes are driven by both transcriptional and post-transcriptional regulators.

Epigenetics

• Epigenetic mechanisms strongly affect gene control.
• Key mechanisms include DNA methylation, chromatin remodeling, and microRNA expression.
• DNA methylation: adding methyl groups to cytosine bases in DNA, affecting transcription factor binding.
• Chromatin remodeling: altering chromatin structure to affect access to DNA for transcription.
• MicroRNAs: small non-coding RNAs that influence mRNA stability and translation.

1-DNA methylation

• DNA methylation involves adding a methyl group to the fifth carbon of the cytosine base.
• 5-methylcytosine (5mC) is frequently near guanine (CpG) sites, often found in CpG islands.
• DNA methyltransferase (DNMT) enzymes catalyze the process of adding the methyl group.
• The cofactor S-adenosylmethionine (SAM) is required.

DNA methylation

• DNA methylation is a covalent modification that often turns off affected genes.
• It does so by attracting proteins that block gene transcription.
• Methylation patterns are often heritable across cell divisions.

Question: How do post-translational modifications like methylation and phosphorylation impact protein functionality?

• Post-translational modifications can alter protein structure and function.

DNA methylation is maintained

• Immediately after DNA replication, each daughter double helix contains one methylated strand and one unmethylated strand.
• Maintenance methyltransferase copies methylation patterns from the parent DNA strand to the daughter strand.

2-Chromatin remodeling-Histone methylation

• Histone methylation and demethylation influence DNA accessibility for transcription.
• Amino acid residues on histones can carry methyl groups to affect the effect of modification.

Acetylation

• Acetylation is the addition of an acetyl group to nitrogen, occurring in almost all eukaryotic proteins.
• N-terminal acetylation happens through cleavage of the methionine by methionine aminopeptidase (MAP).
• N-acetylation is co-translational.

3-Chromatin remodeling-Histone acetylation

• Acetylation at the ε-NH2 of lysine on histone N-termini is related to gene regulation.
• Histone acetylation opens up chromatin structure, increasing accessibility to DNA for transcription factors.
• Histone deacetylases (HDACs) reduce acetylation and close chromatin structure.
• Histone acetylation impacts cellular processes including transcription factors, metabolism, and aging.

Question: What are the three major epigenetic regulators, and how do they influence gene expression?

• These are DNA methylation, histone modifications, and microRNA expression.

3- microRNAs

• MicroRNAs are short RNA molecules (18-24 nucleotides) that control gene expression by binding to mRNAs.
• This binding affects mRNA stability and translation.
• MicroRNAs are involved in various cellular processes.

2-microRNA-directed destruction of mRNA

• Precursor miRNAs are processed into mature, single-stranded miRNAs.
• The mature miRNA binds to recipient mRNAs via RISC.
• The complementary binding either degrades the mRNA or inhibits translation.

miRNAs and environment

• miRNAs control gene and protein expression.
• Environmental factors influence miRNAs expression in development.
• miRNAs are affected by environmental chemicals.
• miRNAs are related to pregnancy-related diseases.

Question: How does DNA methylation affect gene expression, and what role does the enzyme DNMT play in this process?

• DNA methylation usually silences genes via recruitment of proteins that hinder transcription.
• Methyltransferases, for example DNMT1, help maintain existing methylation patterns during DNA replication.

Summary: Epigenetics and the environment

• Epigenetics studies changes in gene expression without altering DNA sequence.
• DNA methylation is critical and can be altered by environmental factors.
• Individual genetic variations influence the responses to environmental exposures.

Epigenetics and the environment

• Large-scale alterations in methylation (gains or losses) are related to environmental exposures and disease.
• Global methylation loss is associated with instability and aging.
• Gains in global methylation are specific to, for example, the placenta and have implications in developmental diseases like Down's syndrome and gestational diabetes.
• Technological advances allow studying epigenetic patterns linked to disease susceptibility.

Gene-Specific methylation

• Recent technologies enable site-specific methylation analysis.
• Environmental exposures (e.g., contaminants and nutrition) have an effect on gene-specific (and global) methylation patterns.
• Gene-specific methylation can reflect disease development and susceptibility.

Gene-Specific Methylation in human

• Methylation changes in humans relate to disease susceptibility.
• For example, prenatal famine exposures show methylation patterns leading to adult disease outcomes (like obesity).

Transcription factors triggered by environmental exposure influence site-specific methylation

• Transcription factors respond to environmental exposures, modifying cellular functions and affecting DNA methylation patterns.
• Activation of transcription factors can inhibit DNMT access and conversely, their repression can enhance DNMT activity.

Question: What are some environmental factors that can lead to changes in DNA methylation?

• Various factors, like air pollutants, arsenic, BPA, and tobacco smoke, modify DNA methylation patterns.

Some environmental triggers for DNA methylation alterations

• Environmental factors trigger changes in global and gene-specific methylation.

1-Aflatoxin B1

• Aflatoxin B1 (AFB1) is a mycotoxin found in peanuts, grain, and corn.
• It is a very strong liver-cancer-causing agent.
• Exposure to AFB1 in Taiwanese populations was linked to lower methylation levels in white blood cells, particularly at CpG sites linked to immune response & growth factors.

2-Air pollution

• Air pollution (e.g. particulate matter, ozone, toxic chemicals, diesel fumes) impacts DNA methylation and specific genes.
• Prenatal exposure has more significant consequences and affects gene expression related to immune response, blood pressure, and development.

3-Arsenic

• Arsenic exposure is linked to altered methylation patterns in adults and infants, including both hypo- and hypermethylation.
• Research suggests that the effects of arsenic exposure on methylation can vary by sex.
• Arsenic exposure has been linked to health issues such as cancer and diabetes in human populations.

4-Bisphenol-A (BPA)

• BPA is a widespread environmental chemical.
• Exposure has shown to affect methylation patterns (particularly hypomethylation) in women and young girls (fetal exposure impacts liver).
• Alterations in methylation are observed across various tissues, including the placenta and fetal liver/kidney.
• BPA targets chromosome X and affects methylation linked to metabolism, transport, and immune functions.

5-Tobacco smoke

• Tobacco smoke affects genomic stability and the epigenome.
• Both in-utero and adult exposure to tobacco smoke lead to hypomethylation.
• Tobacco smoke exposure changes DNA methylation patterns, influencing genes associated with cancer, metabolism, and fetal development.
• Specific genes like those involved in cell division and metabolism are affected.

6-Nutritional factors

• Early nutrition and prenatal nutrients are closely linked to developmental programming and long-term health.
• Nutrients like folate, methionine, betaine, and choline impact global and specific methylation patterns.
• Nutritional factors can influence the epigenetic profile of offspring.
• Nutritional factors can moderate effects from environmental contaminants

Question: What are the major gaps in epigenetics research, and how might addressing these improve our understanding of gene regulation?

• Major gaps include identifying how environmental mixtures, sex-specific effects, tissue-level specificity, and long-term stability affect epigenetic regulation.
• Improving the field requires more advanced research techniques, including longitudinal studies of large populations and tissue-specific studies.

Future directions

• Environmental mixtures analysis (complex interactions of contaminants)
• Sex-specific effects
• Tissue specificity
• Stability and functional consequences of methylation over time

Conclusion

• A dynamic connection exists between environmental exposure and the epigenome.
• Epigenetic research has strong implications for health comprehension and development of personalized prevention/treatment strategies.

Explore the fascinating world of the epigenome through this quiz. Discover its definition, significance, and impact on genetics and cellular function. Perfect for anyone looking to deepen their understanding of molecular biology.