Samenvatting van hoorcolleges Applied Nutrigenomics HNH-34806 Wageningen University WUR. Bevat e-module over epigenetica en hoorcolleges over GWAS, transcriptomics, metabolomics, het microbioom en nutrigenomics.
Genetics versus epigenetics
Genetics: heritability of the DNA sequence
Genome: all genes together; unique for any individual, except for monozygotic (identical) twins
2003: whole human genome was sequenced
It was expected that this would provide the information required to understand the origin and development of
all diseases
This was not true, because epigenetics forms an additional layer of information which helps determining
phenotype from genotype
Epigenetics determine the phenotype
Different organs and tissues all contain the same DNA sequence; the epigenome differs from tissue to tissue,
controlling the expression of genes and providing specific identity to each cell type
→ when identical twins age, the patterns of epigenetic modifications are diverging; impact phenotype
Environment also has impact on epigenetics and therefore phenotype
Epigenetic from a mechanistic perspective
DNA in one cell: 2 meters long
Epigenetic mechanisms as DNA methylation and histone modifications are involved in DNA packaging
Nucleosome: NDA wrapped around 8 histones (combination of H2A, H2B, H3 and H4)
H1: linker histone: binds nucleosome at the entry and exit of the DNA; locking it into place
H3 and H4: long tails that stick out from the nucleosome; histone modifications usually occur at these histones
(but core histones can also be modified)
Chromatin: multiple nucleosomes → chromatin fibres make a chromosome
→ state of nucleosomes and chromatin is important for gene transcription
1. Heterochromatin: DNA condensed, cannot be transcribed dark under microscope
2. Euchromatin: open chromatin, can be transcribed light under microscope
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,Epigenetic modifications
Epigenetics: study of inherited changes in gene expression caused by mechanisms other than changes in the
underlying DNA sequence
▪ DNA methylation
• Addition of a methyl group to a cytosine
• Works together with histone modifications to establish gene silencing
▪ Histone modifications
• Euchromatin: accessible for transcription
• Heterochromatin: transcriptionally silenced
• Facultative heterochromatin: histone state differs per cell type or time; relevant for silencing of genes
• Written histone modification: H3K4me3
- H3: name of the histone
- K4: amino acid abbreviation and its position in the protein
- me: modification; methylation ac: acetylation
- 3: number of modification methyl can replace more than one hydrogen group; 1, 2 or 3
methylated (acetylation cannot do this)
• Histone proteins are positively charged
• DNA is a negative molecule
→ electrostatic interaction keeps it together
1. Histone acetylation
- Acetyl group neutralizes positive histone charge
- Decreases attraction between histones and DNA → euchromatin
- HAT: histone acetyltransferase; adds acetyl group to histone accessible for transcription
- HDAC: histone deacetylase; removes acetyl group from histone not accessible for transcription
2. Histone methylation
▪ Non-coding RNAs
• Less than 2% of transcripts are coding for genes
• Non-coding RNAs
- Small ncRNAs; siRNAs, miRNAs, piRNAs
→ involved in transcriptional and post-transcriptional gene-silencing
o Binding to mRNA: affecting its stability or targeting it for degradation → preventing mRNA to be
translated to protein
- Long ncRNAs: longer than 200 nucleotides in length
o Signal: indicates gene regulation in space and time
o Decoy: titrate away transcription factors and other proteins from chromatin
o Guide: recruitment of chromatin modifying enzymes to target genes
o Scaffold : brings together multiple proteins to form ribonucleoprotein complexes and affects
histone modifications
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,DNA methylation: what and where?
DNA methylation
▪ DNA methylation is mutagenic!
▪ At 5th position of the heterocyclic aromatic ring from cytosine normally there’s a hydrogen
▪ -H → -CH3 5-methylcytosine
▪ Methylation occurs almost exclusively in the context of paired symmetrical methylation of a CpG dinucleotide
= CpG site
→ dinucleotide = two nucleotides attached by a phosphate bridge
▪ 70-80% of CpG sites are methylated 2-8% of all cytosines
Non-random distribution of CpGs in genome
▪ CpG rich and CpG poor sites in genome majority CpG-poor
▪ C and G nucleotides underrepresented A and T overrepresented
▪ CpG sites underrepresented compared to other dinucleotides
▪ Methylated cytosine → [accidental deamination] → thymine
→ repaired by mismatch repair very inefficient
▪ Unmethylated cytosine → [deamination] → uracil
→ repair very efficient
▪ Ancestral genome; CpG more randomly distributed
▪ During evolution
• Methylated CG sequence → TG sequence not repaired
• Unmethylated CG sequence → UG sequence repaired
→ deficiency in CG sequence in current human genome
▪ Species with heavily methylated genome (vertebrates) have low CG density and elevation of TG (deamination
product)
CpG islands, shores and open sea
CGIs: CpG islands relatively rich CpG areas; 2000 base pairs long with strong enrichment of CpG
dinucleotides
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, ▪ IRSs: interspersed repetitive sequences
▪ Promoter regions
▪ Gene bodies
CpG shores: 2000 base pairs flanking a CGI regions of lower CpG density
Open sea: single CpG sites
Methyl donation and DNA methyltransferases (DNMTs)
SAM: S-adenosylmethionine major methyl donor in the cell
SAH: S-adenosylhomocysteine
HCY: homocysteine
DNMTs: DNA methyltransferases
▪ DNMT1: maintenance methyltransferase during DNA synthesis
→ ideal substrate: hemimethylated sites
▪ DNMT3a and DNTM3b: de-novo-enzymes in development
→ prefer to introduce methylation to only one of the DNA strands; hemimethylated sites
→ ideal substrates for DNMT1
▪ DNMT2: weak DNA methyltransferase activity, actually functions as RNA methyltransferase
▪ DNMT3L: recruits DNMT3a and 3b to targets and increases their ability to bind the methyl groups
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