Gene Expression and Regulation

Gene Expression and Regulation

• Gene expression is the process by which the information in a gene is used to create a protein
• If the gene is active, messenger RNA (mRNA) is transcribed from DNA

The Basics of mRNA

• mRNA's sequence is read in groups of three bases, known as codons
• Each codon corresponds to one of 20 amino acids
• A ribosome slides along mRNA adding appropriate amino acids
• These amino acids are ferried to the ribosme by tRNA

Gene Expression Control

• Polypeptide chains are made by translation
• All cells in the body contain the same set of genes
• Cells can express different subsets of genes
• Cells can also switch genes on or off as needed
• The major on-off controls operate at the level of transcription

Levels of Gene Reguation

• The amount of a particular protein in a cell is regulated at several levels
• mRNA transcription
• mRNA degradation
• Protein translation
• Protein degradation

Gene Expression Profiles

• Only a small fraction of genes are expressed in any particular cell or tissue
• Sets of genes are expressed for proteins that perform specialized functions
• "Gene expression profile" indicates what the cell/tissue does

The Gene Expression Proflie

• To create a gene expression profile you must:
• Obtain samples of tissues of interest
• Decide on the genes of interest
• Measure mRNA levels for those genes
• Compare gene activity profiles in different tissues

Enhancing Gene Expression

• DNA elements in the vicinity of a gene allow control of gene expression
• The promoter region is usually "upstream" of the gene
  • RNA polymerase binds to the promoter region to begin transcribing mRNA
• Enhancer and silencer regions are farther away from the gene
• These bind proteins that activate or reduce transcription

Biological Regulation

• A signal transduction pathway allows extracellular signals to regulate the transcription of genes
• These pathways are necessary for biological processes

Epigenetic Modifications

• Epigenetic/epigenomic modifications allow gene expression profiles to be passed from a cell to its daughter cells
• Epigenetic modifications do not change the DNA sequence
• Epigenetic mean 'Above the genome'

Types of Epigenetic Mechanisms

• The two main epigenetic mechanisms are:
• Direct modifications to DNA (DNA methylation)
• Modifications to DNA packaging (Histone modification)

The Impacts of DNA Methylation

• DNA methylation is a mechanism by which genes may be switched off
• A DNA methylation mark, when incorporated into the DNA of a specific tissue, usually remains unchanged and is considered a permanent modification throughout the entire lifespan of an individual. This stable alteration plays a critical role in regulating gene expression by inhibiting gene transcription in certain regions of the genome, ultimately influencing various biological processes, including cellular differentiation and development.
• In contrast, DNA methylation in gametes—sperm and egg cells—is subject to a unique and thorough erasure process during gametogenesis. This mechanism ensures that methylation patterns are reset, allowing the subsequent generation to start with a clean slate regarding epigenetic modifications. This reset is essential for proper embryonic development, as it enables the newly formed zygote to establish its own distinctive methylation patterns, thus shaping the gene expression landscape specific to that individual.
• The permanence of DNA methylation marks in somatic tissues is vital for maintaining cellular identity and function, whereas the erasure of these marks in gametes underscores the importance of epigenetic reprogramming during reproduction, which facilitates genetic diversity and adaptation in evolving populations.
• This duality in the behavior of DNA methylation reveals its intricate role in both the continuity and variability of genetic information across generations.

The Structure of DNA

• During cell division, DNA in chromosomes is packaged as chromatin
• DNA is wound around proteins called histones
• For transcription to occur, RNA polymerase must be able to access the DNA

How Gene is Transcribed

• Chemical modification of histones near a gene can either allow or prevent its transcription

Epigenomes Over Time

• The epigenome is the full set of chemical modifications in a cell that direct transcription
• By most definitions, the epigenome marks must be passed on through cell division
• Much of the epigenome is passed on to the next generation of cells, helping them to remain specialized
• The epigenome can also develop over time, during embryonic development

Embryonic Development

• Embryonic and fetal development progressively produces more differentiated cells that have different gene expression profiles
• The epigenome determines many of these changes

DNA Methylation

• DNA methylation is important in cellular events through genomic imprinting
• DNA methylation impacts X-chromosome inactivation

What is Genomic Imprinting

• Most of the epigenome is reset during meiosis for the start of a zygote
• Some epigenetic marks are transmitted to offspring anyway
• The main example of this is called 'genomic imprinting' or 'parent of origin' effect

Mechanisms of Genomic Imprinting

• For certain genes, the paternally-derived copy is switched off during sperm development (spermatogenesis)
• For certain other genes, the maternally-derived copy is switched off in egg development (oogenesis)
• The total number of imprinted genes is relatively small (less than 100)

The Effects Fetal Imprinting

• Many imprinted genes are involved in fetal and placental growth
• The active copy for genes increasing growth tends to be from the father
• The active copy for genes decreasing growth tends to be from the mother
• In difficult environmental conditions, limiting nutritional requirement is in the mother's best interests
• The father can maximize the nutrition of his progeny
• This imbalance has been dubbed the "battle of the sexes"

Summary of Epigenetics

• Gene expression is regulated mainly by regulating by control of mRNA transcription
• Different tissues have different gene expression profiles
• An 'epigenetic mark' switches off transcription of genes
  • Epigenetic marks are also transmitted through cell division to daughter cells
• Epigenetic mechanisms include DNA methylation and histone modification
• The zygote starts with few epigenetic marks, but marks are added during embryonic development to regulate tissue differentiation

Aging and Epigenetics

• Epigenetic marks are added throughout life
• Epigenetic signatures correlates well with chronological age with the 'epigenetic clock'
• The epigenome refers to the full set of epigenetic marks in a cell
• Imprinted genes are the only genes that are epigenetically switched off in gametes
  • This switching off is determined by the parent of origin (father or mother)
• Dosage compensation occurs for the extra X-chromosome in females
• The Lyon hypothesis states the compensation occurs by random inactivation of one X-chromosome in early embryonic development
• These mechanisms determine the nature of X-linked inheritance
• X-linked 'recessive' inheritance is involved in red-green colour blindness