Epigenetics Exam I Flashcards
Epigenetics was first defined by whom?
Conrad Waddington in 1942 as a branch of biology which studies the casual interactions between genes and their products which bring the phenotype into being
Gene Regulation describes what?
How genes are controlled
How do they know what tissue they are in
How do they know what type of cell they are
How do you maintain cell identity and function
Current definition of Epigenetics
Study of changes in gene function that are mitotically and or meiotically heritable and that do not entail a change in the DNA sequence
The change in gene function without change in DNA sequence
Changes in phwnotype not caused by changes in DNA
Heredity
transmission of traits from parents to offspring
Heritability
genetic variance / phenotype variance
How does epigenetics work?
control gene expression acheived through semi reversible covalent modification of DNA bases and the proteins that package DNA and the proteins in the surrounding area of the of the nucleus
Major theoretical challenge
inheritance of acquired characters
Gene Regulatory Network
hard wired
genetic relationships between DNA sequences and their products
Attractors
in dynamic system, a set of physical properties toward which a system tends to evolve regardless of starting conditions of the system.
Chromatin Structure
DNA interaction with histones and non histone proteins produces suffiecient level of compaction to fit into a cell nucleus
Chromatin
generic term for any complex of DNA and protein found in a nucleus of a cell
Chromosomes
separate pieces of chromatin that behave as a unit during cell division. Versatile, modular strucutre for packaging DNA that supports flexibilty of form and funciton
Nucleosome
Basic unit of chromatin DNA, histones, non histone protein Package , hold DNA Where a particular locus is in 3D inside the nucleus Formed from a histone octamer and DNA
Histones
Proteins
H1,H2,H2B,H3,H4
Like stacked blocks
H1 holds end of DNA after it has wrapped around octamer
Major types of Chromatin Structure
Heterochromatin
Euchromatin
Heterochromatin
highly condensed, usually inactive transcriptionally
Types of heterochromatin
constituitive and falcutative
Constitutive
condensed in all cells
Facultative
Condensed in only some cells and relaxed in other cells
Euchromatin
relaxed, usually active transcriptionally
How can chromatin structure affect transcription?
Hetero- reduces transcription
Nucleoomes can sequester promotersm make them inaccessible to RNA polymerase and transcription factors
Changes can be inherited from gen to another
Faithfully transmitted through mitosis
Mechanisms that can regulate chromatin patterns
Histone modifications
- N terminal tails of histones H3 and 4 can be modified
- Methylation, acetylation, phosphorylation, ubiquination
- Affect nucleosome interaction with other nucleosomes and with regulatory proteins
- Affect higher order chromatin structure
Histone variants can cause diferent nucleosome structures
Remodeling complexes can alter nucleosome patterns: change accessibility of promoter sequences and remove or reposition promoter blocking nucleosomes
Chromatin Remodeling
ATP dependent nucleosome remodeling factor that modulates acces of transcription factors to DNA
Chromatin Remodeling Structures- recruited to particular regions by site specific DNA biding proteins, reposition of nucleosomes
Chromosome Modificatio n
spontaneous nucleosome conformation changes
Epigenetic modification of DNA and histones regulate?
nucleosome occupancy and repositioning- histone modification and DNA methylation
Histones
proteins that package DNA
Comprise the Histone Octamer
H2A, H2B,H3,H4
that wrap 147 bp of DNA
Fundamental unit of nucleosome
Runs between nucleosomes
Linker DNA
held by H1
Negative charge of DNA is held by what?
positive charge of Amide group in histone AA
What are core octamer and associate DNA
histone chaperones and other proteins that assemble the histone
Types of histone modification
Non covalent modification
Covalent modification
Non covalent modification
effects how DNA interacts with the histone proteins leading to the relocation of the histones on DNA
Covalent Modification
effects positioning of histones but does so through modification of the N terminal tails particularly the H3 and 4 tails
Major types of modification that effect trasncription
Acetylation
Methylation
Phosphorylation
Small role in transcription
Ubiquination
Sumoylation
Ribosylation
Chromatin remodeling
proteins that act to change structure
Chromatin Modification
spontaneous nucleosome conformation changes- not understood
SRCAP
Enzyme regulated in concert with androgen receptor
Catalyzes H2A.Z and H2B
Deregulation can lead to cancer
H2A.Z
Histone variant
Different version of h2a
Different DNA sequence
H2A.Z 1 and 2 , variable versions of H2A.Z
Histone variants
Genetically different
May cause epigenetic differences
Different AA sequences
Histone PTM
Acetylation
Methylation
Can occur at the same time
Histone variants and PTAs
Cancer has what kind of causes and effects?
Epigenetic and Genetic
Epi- DNA methylation and history modification , histone variants
Known to associate with cancer
Histone and histone PTM
DNA replication dependent histones
H1,2 a and b, 3, 4 Exist in gene clusters Massively expressed during s phase No poly a tail or introns Several variants exists
DNA replication independent
H1,2 a and b, 3, 4 Lower expression Has poly a tail and introns Expressed throughout cell cycle Replacement histone variants that replace one or more of the independent ones in certain nucleosomes
Types of PTM
Long range - PTM that occurs commonly throughout the cell/genome
Specific - occur at particular loci / gene
H2A.Z
Ancient replacement variant - present in yeast
Encoded by a single gene throughout vertebrates
Needed for survival in model organisms
Acts as depressor and activator
Helps recruits RNA poly II
Poising genes for expression
Not necessary for transcription
Tx activation requires evicting h2a.z containing nucleosomes near tss
H2A.Z-1 and 2
Different promoters, 5’utr , intron/exon organization, differ by three amino acids
Homotypic
Nucleosomes octamer with 2 identical h2a
Heterotypic
Nucleosomes octamer with 2 different h2a
Histone H2A.Z PTM
H2a.z being activator or repress or depends on PTM
of h2a.z or other histones in nucleosomes including h2a.z
H2a.z acetylation found in promoters of actively transcribed genes
Non acetylation in poised promoters of genes not being transcribed
Relationship between PTM and gene expression
