Epigenetics of Human Disease Exam 1
Questions and answers
Genetics - ✅✅The science studying the mechanisms of inheritance in general and genes in particular
Epigenetics - ✅✅- The control of gene expression that is not
accompanied by changes in DNA sequence
- Mechanisms of heredity which do not involve modification to DNA sequence and are reversible in
nature
- The study of mitotically and/or meiotically heritable changes in gene function that cannot be explained
by changes in DNA sequence
Key points from Lecture 1 - ✅✅• Epigenetics does not involve changes to the DNA sequence
• Environment is key to epigenetics
• Lamark and Darwin were not (completely) wrong
- Acquiredtraitscanbepassedon
• likely via epigenetics
- Darwin's Theory of Pangenesis may explain modern day miRNAs and exosomes as well as other means
of cell-to-cell communication
• Recognize the difference between soft and hard inheritance
• Monumental discoveries in epigenetics
- Position effect
- X-chromosome inactivation
- CpG islands
- Heritability of DNA methylation
- Paternal/maternal allele effects (imprinting) - RNAi
- Histone modifications (PTM and variants)
Chromatin - ✅✅• DNA is not "naked" in eukaryotes
• DNA exists as an intimate complex with specialized proteins - chromatin
,• Originally thought of as a passive packaging molecule
• Now we know of many distinctive forms of chromatin
- covalent and non-covalent mechanisms
Nucleosome - ✅✅fundamental repeating unit of chromatin
The Chromatin Template - ✅✅1. Protein octamer
• Two molecules of each canonical histone (H2A, H2B, H3 and H4)
• Core proteins are small and highly basic
- Globular domain - Flexible tail
• Highly conserved from yeast to human
2. 147 bp of DNA wrapped around the octamer
Histone modifications - ✅✅• Acetylation
• Methylation
• Phosphorylation
• Ubiquitination
• Sumoylation
• ADP-ribosylation
• Biotinylation
• Proline isomerization
Establishing and removing histone modifications - ✅✅• Histone tail modifications are established or
removed by catalytic enzymes
- enzymes reside in large multi-subunit complexes
Much more complicated than a single modification - ✅✅• Modifications occur in combination
• Most correlate with activating or repressive functions
Cis-Effects - ✅✅of covalently modified histone tails
- Changes in physical properties of modified histone tails
• Electrostaticchargeoftail
- Alters inter-nucleosomal contacts
, Acetylation - neutralizes positive charges of highly basic histone tails
• Generatesalocalexpansionofchromatinfiber,enablingbetteraccess of transcription machinery to the
DNA
Phosphorylation - adds net negative charge • Altersnucleosomepackaging
• Exposeshistoneaminotermini
Addition of bulky adducts
• Ubiquitin and ADP-ribose
• Opens up nucleosome arrays
Trans-Effects - ✅✅• of covalently modified histone tails
- Recruitment of binding partners to the chromatin
• Reading covalent histone marks in a context dependent fashion
• Binding partners have an affinity for specific tails
1. Bromodomain
• Recognizes acetylated histone residues
2. Chromodoamin
• Recognize methylated lysine residues
Posttranslational modification enzymes - ✅✅• Writers
- Acetyltransferases
- Methyltransferases
- Kinases
- Ubiquitinases
• Removers (erasers)
- Deacetylases
- Demethylases
- Phosphatases
- Deubiquitinases
Questions and answers
Genetics - ✅✅The science studying the mechanisms of inheritance in general and genes in particular
Epigenetics - ✅✅- The control of gene expression that is not
accompanied by changes in DNA sequence
- Mechanisms of heredity which do not involve modification to DNA sequence and are reversible in
nature
- The study of mitotically and/or meiotically heritable changes in gene function that cannot be explained
by changes in DNA sequence
Key points from Lecture 1 - ✅✅• Epigenetics does not involve changes to the DNA sequence
• Environment is key to epigenetics
• Lamark and Darwin were not (completely) wrong
- Acquiredtraitscanbepassedon
• likely via epigenetics
- Darwin's Theory of Pangenesis may explain modern day miRNAs and exosomes as well as other means
of cell-to-cell communication
• Recognize the difference between soft and hard inheritance
• Monumental discoveries in epigenetics
- Position effect
- X-chromosome inactivation
- CpG islands
- Heritability of DNA methylation
- Paternal/maternal allele effects (imprinting) - RNAi
- Histone modifications (PTM and variants)
Chromatin - ✅✅• DNA is not "naked" in eukaryotes
• DNA exists as an intimate complex with specialized proteins - chromatin
,• Originally thought of as a passive packaging molecule
• Now we know of many distinctive forms of chromatin
- covalent and non-covalent mechanisms
Nucleosome - ✅✅fundamental repeating unit of chromatin
The Chromatin Template - ✅✅1. Protein octamer
• Two molecules of each canonical histone (H2A, H2B, H3 and H4)
• Core proteins are small and highly basic
- Globular domain - Flexible tail
• Highly conserved from yeast to human
2. 147 bp of DNA wrapped around the octamer
Histone modifications - ✅✅• Acetylation
• Methylation
• Phosphorylation
• Ubiquitination
• Sumoylation
• ADP-ribosylation
• Biotinylation
• Proline isomerization
Establishing and removing histone modifications - ✅✅• Histone tail modifications are established or
removed by catalytic enzymes
- enzymes reside in large multi-subunit complexes
Much more complicated than a single modification - ✅✅• Modifications occur in combination
• Most correlate with activating or repressive functions
Cis-Effects - ✅✅of covalently modified histone tails
- Changes in physical properties of modified histone tails
• Electrostaticchargeoftail
- Alters inter-nucleosomal contacts
, Acetylation - neutralizes positive charges of highly basic histone tails
• Generatesalocalexpansionofchromatinfiber,enablingbetteraccess of transcription machinery to the
DNA
Phosphorylation - adds net negative charge • Altersnucleosomepackaging
• Exposeshistoneaminotermini
Addition of bulky adducts
• Ubiquitin and ADP-ribose
• Opens up nucleosome arrays
Trans-Effects - ✅✅• of covalently modified histone tails
- Recruitment of binding partners to the chromatin
• Reading covalent histone marks in a context dependent fashion
• Binding partners have an affinity for specific tails
1. Bromodomain
• Recognizes acetylated histone residues
2. Chromodoamin
• Recognize methylated lysine residues
Posttranslational modification enzymes - ✅✅• Writers
- Acetyltransferases
- Methyltransferases
- Kinases
- Ubiquitinases
• Removers (erasers)
- Deacetylases
- Demethylases
- Phosphatases
- Deubiquitinases
