Epigenetics and Post-Translational Modifications

Environmental Influences on the Epigenome

• Epigenetics studies heritable gene changes not due to DNA sequence alterations
• Epigenetic machinery influences gene expression by affecting mRNA and protein levels
• Epigenetic regulation enables organism-level adaptation to the environment
• Three major epigenetic regulators are: histone modifications, DNA methylation, and non-coding RNA expression

Post-Translation Modifications

• Post-translational modifications (PTMs) add variations to proteins in the proteome—proteins made from genes, changing how much protein there is.
• Examples of PTMs: methylation, acetylation, phosphorylation, glycosylation
• PTMs can affect protein folding, stability, localization, function, activation, and interactions

Diversity and Complexity of Proteins

• Post-translational modifications (PTMs) are chemical changes that modify protein function
• PTMs affect activity, localization, and interactions with other molecules like proteins, nucleic acids, lipids, and cofactors

PTMs Increase Proteome Diversity

• Human genome (21,000-22,000 genes), and human proteome comprises over 1 million proteins
• Single genes may encode multiple proteins through genomic recombination, alternative promoters, differential transcription termination, and alternative splicing.
• PTMs further extend proteome complexity from the genomic level

Epigenetics

• Changes to gene function that are not due to DNA alterations
• Heritable changes caused by transcriptomic and post-transcriptional regulators

Epigenetic Mechanisms

• DNA methylation – adding methyl groups to cytosines in DNA; often inhibiting transcription factors from binding to DNA
• Chromatin remodeling (histone methylation, acetylation/deacetylation) altering the structure of chromatin, affecting the accessibility of DNA to transcription factors.
• MicroRNAs (small non-coding RNAs) influencing gene expression post-transcriptionally

1-DNA Methylation

• Methylation is the addition of a methyl group to a cytosine nucleotide.
• The methyl group is added to the cytosine.
• After replication, maintains the methylation pattern

2-Chromatin Remodeling- Histone Methylation

• Histone methylation and demethylation influence the accessibility of DNA for transcription.
• Methyl groups attached to amino acid residues on histones affect chromatin structure.
• Modifying histones influences gene regulation.

Acetylation

• Chemical modification transferring an acetyl group to a nitrogen in protein, a reversible process in eukaryotic proteins.
• N-terminal acetylation, a co-translational process, attaching an acetyl group to the N-terminus of a polypeptide chain (while still binding to ribosomes), has unclear biological significance.

3- Chromatin Remodeling-Histone Acetylation

• Acetylation of lysine residues on histone N-terminals, regulating gene expression.
• Acetylation (adding acetyl groups) and deacetylation (removing acetyl groups) of histones by HATs and HDACs.
• Histone acetylation and deacetylation have a well-established link to aging and various neurological and cardiovascular diseases

MicroRNAs

• Small non-coding RNAs that influence gene expression
• miRNAs form double-stranded precursor molecules in the nucleus.
• miRNAs are processed to a mature, single-stranded miRNA.
• miRNAs associate with proteins in a complex (RISC).
• This RISC complex searches for complementary sequences on mRNA transcripts;
• mRNA is either targeted for degradation or translation suppression

miRNAs and Environment

• miRNAs are essential epigenetic regulators, impacting gene and protein expression.
• These miRNAs play a key role in development, are sensitive to environmental chemicals, and are involved in pregnancy-related diseases.

Environmental Factors Influencing DNA Methylation

• Environmental exposures (e.g., air pollution, metals, toxins), specific contaminants, nutritional factors, and lifestyle factors influence methylation patterns.
• These factors can impact both global and gene-specific methylation.

Gene-Specific Methylation

• Site-specific methylation is measured in addition to global methylation.
• This provides insight into disease development.
• Studies show that exposing mice to environmental contaminants and/or specific nutrition influences gene methylation that correlates with adult health and disease, including patterns in prenatal development.

Gene-Specific Methylation in Humans

• Studies show that alterations in methylation at a single gene locus can influence disease susceptibility and future health outcomes.
• Studies using Dutch Hunger Winter data demonstrate how famine exposures can lead to variations in prenatal methylation patterns affecting later-life health.
• A single alteration in methylation could impact susceptibility to disease in adults.

Transcription Factors Triggered by Environmental Exposure Influence Site-Specific Methylation

• Environmental contaminants can trigger activation, or repression, of transcription factors as a cellular defense response.
• Specific transcription factors can influence methylation patterns at particular sites in the genome by impacting the activation/inhibition of methyltransferases (DNMTs), resulting in either hypermethylation or hypomethylation.

Environmental Factors Causing Changes in DNA Methylation

• A wide variety of factors like air pollution, toxic metals, and specific chemicals can induce changes to DNA methylation. Exposures to different substances may affect DNA differently in men than women, and at certain life stages, like prenatal development

Nutritional Factors

• Nutritional factors (e.g., folate, methionine, betaine, choline) can modify global methylation levels.
• Paternal intake of these factors influence global methylation, impacting later-life health, specifically in young offspring.
• Diet and nutrient intake impact gene methylation status; specific genes and outcomes like obesity and various diseases have been associated with changes in methylation influenced by nutritional statuses and patterns in intake.

Future Directions in Epigenetics Research

• Further research is needed on the joint impacts of multiple environmental factors on methylation
• Research should include sex-specific effects and tissue-specific methylation patterns to tailor more precise assessments and interventions.
• Evaluating the long-term stability of methylation changes and its effect on gene expression is crucial.

Conclusion

• There's a strong link between environmental influences, particularly nutritional factors and those specific chemical exposures, through exposure-associated DNA methylation.
• Understanding epigenetic principles is important for developing preventive health strategies.

This quiz explores the crucial aspects of epigenetics, including how environmental factors influence the epigenome, and the role of post-translational modifications in protein function. Test your knowledge on histone modifications, DNA methylation, and various PTMs such as methylation and phosphorylation. Gain a deeper understanding of how these processes contribute to the diversity and complexity of proteins.