Presentation on theme: "Shelley Berger The Wistar Institute University of Pennsylvania Overview of Histone Variants Bio 483 October 9, 2012 Shelley Berger Biology; CDB; Genetics."— Presentation transcript:
Shelley Berger The Wistar Institute University of Pennsylvania Overview of Histone Variants Bio 483 October 9, 2012 Shelley Berger Biology; CDB; Genetics Penn Epigenetics Program
Lecture Outline What are histone variants? Review nuclesome structure wrt replacement Consideration of following issues: - sequence variation - nucleosome structure - genome function - location within the genome - physiological function DiscussH2A: macroH2A, H2A.Bbd, H2Ax, H2AZ H3: CENPA, H3.3 testes histone variants
Core vs. variant histones H3 H4 H2A H2B globular NC Are there additional histones?
New nucleosome formation: after replication H3/H4 tetramer binds to DNA 2 dimers H2A/H2B bind H3/H4 tetramer
How to replace? 1.During replication assemble with variant histones 2.H2A/H2B dimer exchange 3.Disassembly of nucleosome during DNA damage repair, transcription
H2A H2B H3 H4 DNA repair Gene repression X chrom inact Gene activation Centromere identity Gene activation
Chromatin compaction by macroH2A
Chromatin destabilization by H2A.Bbd
H2Ax H2A Histone H2Ax in DNA damage pathway
DNA damage leads to complex repair pathways
Molecular details of DNA repair
H2Ax evolutionary conservation
H2Ax phosphorylation is an early step in the repair process
Histone H2AZ (= HTZ1): How does it affect NCP structure and positioning? What is its localization in the genome? What genomic process does it regulate? Histone H2AZ in gene regulation
Genome-wide view of H2AZ at promotors TSS Nuc “Depleted” Region Gene ORF Promoter TSS H2AZ tends to occur in one nuc up- and one nuc down-stream of the TSS Does it regulate transcription?
H2AZ is released as genes are activated Its release is required for full activation
Association of H2A/H2AZ with chromatin H2AZ is more loosely bound to chromatin (although NCP structure very similar) Is there a difference in nucleosome stability?
What is the localization of H2AZ around active/inactive genes? Active genes less enriched than inactive
H2AZ How does it affect NCP structure and positioning? What is its localization in the genome? What genomic process does it regulate? Inactive promoters Poises genes for activation Destablizes NCP: correlates with depletion of one NCP over the TSS How is it incorporated? …a digression
Nucleosomes can be changed in detailed association with DNA, position, presence ATP-dependent Nucleosome Remodeling
Activities of ATP-dependent chromatin remodeling enzymes ATP ADP + P i ATP Remodeler