Role of Chromatin in Cancer

Presented by-Rana Das

BSM/12/10Medical Biotech, Sem VII

What is Chromatin?

Chromatin-structure• Chromatin - a nucleoprotein complex

• protein:DNA = 2:1 mass ratio• histone:DNA = 1:1 mass ratio

• Several levels of condensation• like beads-on-a-string• 30 nm condensed fiber

• Structural units• primary structural unit.• secondary level of compaction, • tertiary structures (such as chromonema fibers).

Multiple levels of chromatin folding

Chromatin compaction and the activity of DNA in transcription

Facultative Heterochromatin

• Heterochromatic at certain times in the cell cycle but are not always this way.

• This is contrasted with constitutive heterochromatin.

• Facultative heterochromatin represents domains of euchromatin.

• An excellent example: Inactive X-chromosome.

Chromatin Staining

• Euchromatin region- lightly stained.

• Heterochromatin region- darkly stained.

• Both chromatins are stain in G-banding.

The Histones• The histone fold• Three-helix core domain

• Octamer• Assembly: H3-H4 tetramer +2 H2A-H2B dimers

• Tails• Disordered N-terminal and or C-terminal tails

Histone arrangement

Histone Modifications

• Histone modifications reported to date include • Acetylation, • Methylation, • Phosphorylation,• Ubiquitination• ADP ribosylation,• Sumoylation.

The substrates:Histone tails - multiple modifications

Black = Arginine (R) methylation (Me) Red = Lysine (K) methylation (Me)Ac= AcetylationP= PhosphorylationAbove ≈ activationBelow ≈ repression

Consequences of Histone modification

H3K4Me2H3K4Me3 Open Chromatin and active gene expressionH3K9Me1

H3K27Me2H3K27Me3H3K9Me2 Inactive Chromatin and repression of gene expressionH3K9Me3

Acetylation is typically associated with transcriptional activation of genes.

Factors involved in Cancer

• Heterochromatin Protein 1 (HP1)

• Histone Acetyltransferases (HATs)

• Histone deacetylases (HDACs)

• Histone Methyl transferases (HMTs)

Heterochromatin Protein 1 (HP1)

• highly conserved proteins.

• Functions- 1. gene repression by heterochromatin formation. 2. transcriptional activation.

• HP1 proteins are fundamental units of heterochromatin packaging that are enriched at the centromeres and telomeres of nearly all Eukaryotic chromosomes.

Histone Acetyltransferases (HATs)

• Catalyze the transfer of acetyl groups.

• Two main groups: A-type and B-type HATs• A-Type HATs catalyze trx-related acetylations• B-Type HATs are cytoplasmic and catalyze acetylations linked to

transport of newly synthesized histones from the cytoplasm to the nucleus

• HDACs: histone deacetylation is catalyzed by HDACs.

Histone Methyl transferases (HMTs)

• histone-modifying enzymes.

• Catalyze the transfer of methyl groups.

• attachment of methyl groups occurs predominantly at specific lysine or arginine residues on histones H3 and H4.

• HDMs: Removes methyl group.

Chromatin and cancer progression• Post-translational modifications of histones.• Different levels of HP1.

Chromatin and cancer progression

• Folding of the chromatin fiber.

• HDAC1 was shown to associate with the tumor suppressor retinoblastoma protein (Rb).

• Histone modification patterns predict prognosis in multiple cancers.

Heterochromatin and Cancer progression

Examples

• Breast Cancer Moderate to low levels of H3K18ac, and H4K12ac, as well as, H3K4me2, H4K20me3, and H4R3me2.

• Prostate Cancer Two histone modifications, H3K4me2 and K18ac.

• Leukemia Dyslocalizatoin of histone deacetylase 1 (HDAC1)

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