Epigenetics of cancer Vilja ja Mia.

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Presentation transcript:

Epigenetics of cancer Vilja ja Mia

Short summary Introduction to epigenetics (in cancer) Epigenetical alterations in cancer vs. normal cells (DNA methylation and histone modifications, full epigenomes) Disruption of the epigenetic machinery Using epigenomic marks in therapeutic targets: to identify cancer cell marks, tumor prognosis, chemotherapy sensitivity Some future ideas in cancer epigenomics

What is epigenetics? = Mitotically or meiotically heritable changes in gene expression that don’t involve a change in DNA sequence. Molecular modifications in chromatin: DNA methylation: 5’ Cytosines in CpG Histone modifications: Histone tail (H3, H4) acetylation, phosphate groups, methylation = “Histone code” non-coding RNA’s: miRNA, siRNA… Chromatin remodeling: protein complexes, SWI-SNF

Epigenetic marks in normal and cancer cells Dependent on cell/tissue type! DNA methylation: CpG islands: transcription starting sites (UTR-areas): hypo-/hypermethylation imprinting (X-inactivation): hypermethylation Repetitive sequences: Transposable elements: hypermethylation Histone modifications: Acetylation: HAT/HDAC- enzymes Methylation: H3K4me3: near the transcription start sites Phosphorylation, Ubiquitylation, Sumoylation

Formation of cancer cells by epigenetical changes

DNA methylation:

Histone modifications:

The epigenomes of cancer cells All epigenetical modifications taken together in certain cell type (Epigenetical pattern of cell) DNA methylation at promoter areas: cell-cycle inhibitor p16 DNA repair genes: MLH1, BRCA1 Tumor-suppressor genes (next picture) Methylation patterns vary among tumor types

The epigenomes of cancer cells 2. Histone modifications: Often associated with DNA methylation (CpG islands) H4: loss of monoacetylation and trimethylation

Disruption of the epigenetic machinery Genes involved in epigenetic modifications are often disrupted in cancer  preliminary data available about those genes

The future of cancer epigenomics Creating epigenome maps: Using epigenomic profiles as cancer cell markers Tumor prognosis Predicting chemotherapy/drugs response Re-expression of silenced genes (therapeutic use)  Creating human epigenome!

References Esteller M., Cancer epigenomics: DNA methylomes and histone modification maps, Nature Reviews, April 2007 Jirtle L.J et al., Environmental epigenetics and disease susceptibility, Nature Reviews, April 2007 Pierce, B.A.: Genetics, a conceptual approach. W.H. Freeman and Co Illustrating how epigenetics can control physical traits, the slimmer and browner of these mice, carrying a gene called agouti, were born to mothers that ate more DNA-methylating foods. Credit: Jirtle/Environmental Health Perspectives

Class activation Let’s play hangman!!! (=hirsipuu)

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