Chromatin Modifications and Epigenetics in Human Disease

Epigenetics (表观遗传学)

• Epigenetics: the study of heritable changes in gene expression that do not involve changes to the underlying DNA sequence

How is epigenetic information encoded?

• DNA methylation
• Location of nucleosomes
• specific histone
• histone modifications (on histone tails)

DNA regulatory elements Recap:

• Promotors: Control direction and amount of transcription
• Enhancers: Increase transcription
• Silencers: Set the boundaries of enhancer activity

DNA methylation

Facts：

• Cytosine (C) bases (胞嘧啶碱基, a pyrimidine base found in DNA and RNA) can be methylated (甲基化, the addition of a methyl group to a molecule)
• Mostly occurs at CpG sites

(CpG site: a pair of cytosine and guanine nucleotides that are located next to eachother)

• Regions with high CpG density are called CpG islands

• Is performed by DNA methyltransferases (DNMTs, DNA甲基转移酶)

• Causes chromatin condensation and gene repression

• Promotor offen asocciated with CpG islands

• Can prevents transcription factor binding

DNA methylation patterns:

• Methylation leads to chromatin condensation and gene repression
• Differential methylation in imprinting control regions leads to genomic imprinting

imprinting (基因印记，遗传印记): a phenomenon in which the expression of a gene depends on whether it was inherited from the mother or the father

• Changes in methylation patterns during development
• Regulated by CTCF binding - methylation prevents CTCF binding

Wild type: the normal DNA sequence

Imprinting disorders:

• Silver-Russell syndrome: hypomethylation of ICR1, reduced expression of IGF2
• Beckwith-Wiedemann syndrome: hypermethylation of ICR1, increased expression of IGF2
• Angelman syndrome: loss of maternal UBE3A expression
• Prader-Willi syndrome: loss of paternal expression of NDN, SNORD11

Histone modifications

• Histone types: H2A, H2B, H3, H4
• How to read modification names: H3K4me3
  • H3: histone type
  • K4: amino acide modified
  • me3: type of modification

Common Marks

Epigenetic Marks and Genomic Elements

Beagrie, R., & Stolper, R. (2023, Oct 17). CM1.4. Chromatin Modifications and Epigenetic Factors [Epigenetic Marks and Genomic Elements]. University of Oxford.

• H3K36me3: Bodies of actively transcribed genes
• H3K27me3: Promoter and body of transiently/developmentally (Polycomb) repressed genes
• H3K9me3: Promoter and body of strongly repressed genes. Also repeat elements
• H3K4me3: Promoter of actively transcribed and (some) Polycomb repressed genes
• H3K4me1: Enhancers
• H3K27ac: Active enhancers and promoter of actively transcribed genes
• Accessibility: Enhancers, active promoters, Polycomb repressed promoters, insulators
• DNAme: CpGs at Enhancers, active promoters, Polycomb repressed promoters & insulators are demethylated

Chromatin Proteins

• Types of chromatin proteins:
  • Readers: recognize and bind to specific histone modifications
  • Writers: add histone modifications
  • Erasers: remove histone modifications
  • Remodelers: change the position of nucleosomes

Writers can be readers at some mark

Erasers can be readers at some mark

Mutation in theses proteins can lead to disease

Epigenetic diseases:

• Rubinstein-Taybi syndrome: mutation in CBP or P300, intellectual disability, facial abnormalities, broad thumbs and toes