BCH 4101 Lecture 10: Epigenomics
28 Apr 2018
School
Department
Course
Professor
November 8, 2017
Epigenomics
Epigenomics
Looks at the epigenetic changes throughout the whole cell
Epigenetics
C.H. Waddington coined the term “epigenetics”
-Represents changes in the phenotype without changes in the genotype
Epigenetic landscape: epigenetic mechanisms determine which genes will be expressed
-Different phenotypes can be determined by different genetic expression
-Causes cell differentiation
Epigenetics: the structural adaptation of chromosomal regions so as to register, signal, or perpetuate altered activity
states
-Structural adaptation
•Involves condensation of chromatin, chemical modification to histone proteins, changes to the DNA itself (ex.
methylation)
•Can influence an entire chromosome (ex. X inactivation), specific areas (ex. telomere), or a single locus
-Register, signal, or perpetuate
•Can add signalling molecules to histone proteins
•Can perpetuate the signal - epigenetic changes are heritable (daughter cells will inherit epigenetic changes)
-Altered activity states
•Results in transcriptionally active or repressed chromatin
•Most likely affected by compaction of chromatin
Epigenetics and Histones
Histones: more than just a structural role
-Involved in DNA repair, replication, recombination, and regulation of gene expression
-Recall: made of 8 histone proteins
•2 Histone 2A-2B dimers
•2 Histone 3-4 dimers
•Tails stick out of the histone core and are easily accessible for modification
1
November 8, 2017
-NB: there is some new evidence suggesting that the interior of the histone core can be modified as well
Histone Writers
Histone tails can undergo several different types of covalent modification
-Can by modified by “writer” or “eraser” proteins
-Modifications will be interpreted by “reader” proteins, that will translate the code into a specific outcome
Histone code:
-Acetylation
•Decreases positive charges on histone - decreases DNA-histone interactions (DNA is negatively charged)
-Makes nucleosomes more mobile
•Enhances transcription - usually associated with euchromatin
•Catalyzed by histone acetyltransferases (HATs)
-Aka KATs - also acetylate lysine
•Acetylation usually occurs on the tails of histone 3 and 4
•Ex. H3K9, H3K14, H3K18, H4K5, H4K8, and H4K12
-*NB: don’t need to memorize all of these, but remember one or two
-H3K9 and H3K14: associated with gene expression
-H4K12: associated with poor prognosis in cancer
-Methylation
•Occurs primarily on lysine and arginine residues in the histone tails
-Can have mono-, di-, and trimethylated lysine residues
-Can have mono-, asymmetrical di-, or symmetrical dimethyl arginine
•Usually occurs on H3 and H4
•Catalyzed by histone methyltransferases
-Uses SAM (S-adenosyl methionine) as a cofactor
-Contains a SET domain that is important in the methylation process
-NB: different histone methyltransferases will methylate arginine vs. lysine
•Ex. Lysine methylation: H3K9me3, H3K27me3, H3K4me3
-H3K9me3, H3K27me3: associated with gene silencing
•NB: me3 = trimethylation
2
November 8, 2017
-H3K4me3: associated with gene activation
•Ex. Arginine methylation: H3R17me2a, H3R26me2a, H4Rm32a, H3R2me2a
-H3R2me2a: counteracts and overrides the activating H3K4me3
-Phosphorylation
•Usually occurs on tyrosine, serine, threonine, and histidine residues
•Associated with gene expression, chromosome condensation during mitosis, DNA repair
•Phosphorylated by kinases
-NB: same types of kinases activated in the cytosol and nucleus will also be involved in phosphorylating the
histone tails - no kinases for histone tails specifically
-Ex. MSK1 and MSK2 —> MAPK signalling
•Ex. H3Ser10 and H3Ser28 = activated transcription
-β-N-acetylglucosamine: added to serine and threonine on H2A, H2B, H4
-ADP ribosylation: mono- and poly-ADP ribosylated on glutamate and arginine residues
•Correlated with relaxed chromatin state
-Ubiquitination and sumoylation:
•Associated with gene silencing and transcription initiation
•Sumoylation = mostly repressive function (antagonizes acetylation)
Histone Erasers
All histone modifications are reversible
-Histone deacetylases (HDACs): remove acetyl group
-Demethylases: remove methyl groups
-Phosphatases: remove phosphate groups
-Deubiquitylases: remove ubiquitin groups
Contribute to the dynamic nature of chromatin
The Histone Code
Each combination of modifications means something different
Recruitment of histone “readers” —> function
-Readers: proteins that recognize the specific histone modifications via specialized domains
3
Document Summary
Looks at the epigenetic changes throughout the whole cell. Represents changes in the phenotype without changes in the genotype. Epigenetic landscape: epigenetic mechanisms determine which genes will be expressed. Different phenotypes can be determined by different genetic expression. Epigenetics: the structural adaptation of chromosomal regions so as to register, signal, or perpetuate altered activity states. Structural adaptation: involves condensation of chromatin, chemical modi cation to histone proteins, changes to the dna itself (ex. methylation, can in uence an entire chromosome (ex. X inactivation), speci c areas (ex. telomere), or a single locus. Register, signal, or perpetuate: can add signalling molecules to histone proteins, can perpetuate the signal - epigenetic changes are heritable (daughter cells will inherit epigenetic changes) Altered activity states: results in transcriptionally active or repressed chromatin, most likely affected by compaction of chromatin. Involved in dna repair, replication, recombination, and regulation of gene expression.
