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Chromatin Structure &Gene Expression
The Histone Code
Structural Features of DNA
The Genome is Organized into Chromosomes
A. Chromatin fibers exploding from lysed nucleus
B. Metaphase Chromosome (folded fibers).
DNA-Protein Fibers Make up Chromatin
Chromosomes Are made of Thick Chromatin Fibers
Thick Fibers Can Unravel to Reveal Thin Fibers
The Fundamental Chromatin Fiber is the 10 nm Fiber (DNA Associated With Nucleosomes)
30 nm fibers
10 nm fibers :“beads on a string”nucleosome
nucleosome
DNA
Levels of DNA Packing Based on the Fundamental Fiber
Probing the 10 nm Fiber With Nuclease
Nucleosomes Are Composed of DNA and an Ocatamer of Four Histone Pairs + DNA
Nucleosome Structure
DNA
H2B
H4 H3
H2A
H2A Fold H2A/H2B Dimer
Histones Assemble into Core Ocatamer
Final Ocatamer Assembly
Conformations for the 30 nm Fiber
Some Chromatin Allows Access to DNABy Specific Binding Proteins (TF & Pol)
Covalent Modification of the Histone Tails Can Alter DNA- Histone Interaction or “Mark” Nucleosomes
Acetylation (lys)
Methylation (Lys)
Phosphorylation (ser)
Ubiquination (Lys)
Chromatin is Dynamic- Remodeling Complexes Alter Structure or Positioning on DNA
A model for Dynamic Regulation of Chromatin & Access to DNA
Chromatin Remodeling Complexes Like Sir Can Recognize Acetylated Histone Tails
Heterochromatin Inactivates Specific Regions of Chromosomes With Defined Borders (Epigenetic Modification)
Variegated Position Effects Occur When Normally Active Genes Become Heterochromatin~30-40 Loci modify PEV.
•Su(var) Genes suppress variagation.
•HDACs
•E(var) Genes enhance variagation
•Bromo & Chromodomain proteinsBromo domains bind Ac Chromo domains bind Me
Histone Modification May Mark Nucleosomes as Heterochromatin
Is There A Histone Modification Code?
David Allis’ Model For The Histone Code
Active Chromatin Can Become Extended in Looped Domains
Locus Control Region (LCR)
Activation of Promoters By Acetylation & Phosporylation –The Standard Model
A = Activator bound to upstream reg. seq.
HAT = Histone Acetyl Transferase
P = Phosphate
Ac = Acetate
Ki = Kinase
Swi/SNF = Chromatin Remodeling Complex
T = TATA Box
M = Mediator
ChIP Assay
The Histone Code: What do we know for sure? The information required for proper gene
transcription is not just the promotors enhancers and transcription factors
Chromatin structure regulates gene expression Chromatin structure is regulated at different levels
Heterochromatin vs. Euchromatin Nucleosome structure at promoters and other regulatory
sequences Histone modification plays a role in the regulation of
chromatin structure Modification of transcription factors also plays a role We can’t read the code yet!