DNA methylation - Histone variants

10 important questions on DNA methylation - Histone variants

What is a histone variant?

Histone variant are composed of proteins with different amino acid composition that standard/canonical histones

  • encoded throughout the cell cycle, while standard are during S phase

Difference between canonical and variants?

Standard:
  1. expressed during DNA replication
  2. deposited during DNA treplication
  3. encoded by multiple copies, in gene clusters
  4. Genes do not contain introns
  5. Transcripts non-polyadenylated

Histone variant:
  • • Typically expressed throughout cell cycle
  • • Typically deposited replication-independent • Encoded by individual genes
  • • Genes typically contain introns
  • • Transcripts usually polyadenylated

What are the function of some well-known variants?

H3.3 - histone replacement/ mainly active chromatin
CENP-A - centromere function and kinetochore assembly/ centromeric chromatin

H2AX - DNA repair and recombination
H2AZ - gene expression, chromosome segregation/ active/inactive chromatin
macroH2A - transcriptional repression, X-chromosoom inactivation/ inactive chromatin
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What is the function of cenH3 (CENP-A)?

It present at centromeres and crucial for centromere function. It assembly kinetochore structure.
  • CenH3 and H3 incorporation at centromeres alternate, and chromatin forms helical turns

What is the function of H3.3?

During transcription, transiting RNA polymerases displace histones and once in a while one gets lost
  • Displaced H3 histones are replaced by H3.3 histones
  • H3.3 prevents cryptic initiation of transcription!
  • Most transcription occurs in genic regions: hence most H3.3 is incorporated into genic regions

Explain the difference between deposition of H3 and H3.3 into chromatin

H3.1 is deposited during replication and by the CAF-1 histone chaperone.


H3.3 is deposited in a replication- independent manner (during & outside replication.
  • HIRA histone chaperone deposits H3.3 at genes and regulatory sequences
  • Daxx histone chaperone deposits H3.3 at repetitive DNA (heterochromatin)

Why is H3.3 also present at heterochromatin?


H3.3 is also present at a.o. telomeric repeats & pericentric heterochromatin (low levels)

  • In repeated sequences some transcription takes place & histones can also get lost

What is the role of macro-H2A and transcriptional expression?

It correlates with transcriptional repression
  • Macro-H2A (mH2A) is enriched at inactive X-chromosome
  • C-terminal associates with histone deacetylases (HDACs)
    • blocks nucleosome remodeling
    • font-sizefont-familyActs as tumor suppressor t font-sizefont-familyin cancer

What is the function of H2A.B?

  • Enriched at active X chromosome
    • Results in less stable nucleosomes that are more accessible to transcription factors & RNA pol II

  • Enriched at TSSs of actively transcribed genes & appears to facilitate transcription & play role in mRNA splicing

What are the function of H2A.X?

H2A.X plays important role in double-strand break repair
  • The phosphorylated H2A.X is replaced after DNA repair by non-phosphorylated H2A.X

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