Epigenetics Flashcards
Epigenetics
- Study of heritable changes in gene expression without a change in the actual DNA sequence
- AKA the reason different cell types/tissues look different despite having the exact same DNA
Levels of DNA packaging
- double helix
- nucleosomes
- chromatin fiber of packed nucleosomes
- chromosome
What are the components of a nucleosome?
- 8 histone molecules: 2x H2A, H2B, H3, and H4
- Wrapped with 146 bp DNA
- Nucleosomes connected by linker DNA (H1)
What are the possible modifications that can be made to histones?
- acetylation
- methylaiton
- phosphorylation
- deimination
- ubiquitination
How does histone acetylation impact chromatin structure and transcription?
- Acetylation opens chromatin: acetyl groups are negatively charged and do not want to interact with negatively charged DNA
- This increases gene expression
What enzymes are involved in histone acetylation?
- Histone acetyltransferases (HATs)
- Histone deacetylases (HDACs)
What nucleic acids are methylated?
Cytosine => 5’ methyl-cytosine
What is the effect of methylation on chromatin structure and transcription?
- Hypermethylation = condensed chromatin = less expression
- Hypomethylation = open chromatin = more expression
Where is heterochromatin found, what modifications are present, and how is it transcribed?
- found near chromosome ends or centromeres where there are few genes
- methylated cytosines; deacetylated histone tails
- transcriptional repression
What modifications are present on euchromatin and how is it transcribed?
- Acetylated histone tails; hypomethylation
- transcriptional activation
What are TADs?
- Topolocigally associated domains are genetic neighborhoods
- Genes in a TAD are co-regulated
- TADs are consistent across cell types but their regulations vary
How many chromatin states are there?
15 (more than just open/closed!)
What confers cell-type-specific transcription?
Chromatin state: heterochromatin vs. enhancers vs. TSS’s vs. enhancers
What is role of methylation in development?
- Increasing methylation in prospematognoia and oocyte growth
- Decreasing methylation from fertilization to blastocyst formation
- Increasing methylation throughout embryogenesis as cells begin to differentiate
What are ways in which epigenetics can cause disease?
- Imprinting
- Pathogenic variation in genes that regulate epigenetic machinery
- Pathogenic variation that affects chromatin state
- Cancer
- Transgenerational inheritance
What is Kabuki syndrome?
- Rare neurodevelopmental disorder
- Symptoms include: characteristic facial features, developmental delay, intellectual disability, growth deficiency, skeletal anomalies, congenital heart defects, genitourinary anomalies, seizures
What are the mechanisms of Kabuki syndrome inheritance/occurence?
- Autosomal dominant
- De novo
What are the genetic causes of Kabuki syndrome?
MLL2 (H3 lys 4 methyltransferase):
- normal = methylates = open chromatin and gene expression
- mutated copy = less methylation = closed chromatin and less expression of genes important to development
KDM6A (H3 lys 27 demethylase)
- normal = demethylation = open chromatin and gene expression
- mutated copy = more methylation = closed chromatin and less gene expression
What is CHD2 associated epilepsy?
- most severe pediatric epilepsy
- first few day - years of life
- drop attacks and atonic-myoclonic-absence seizures
- no response to medication
What is the mechanism of CHD2-associated epilepsy inheritance/occurence?
De novo mutation
What is the genetic cause of CHD2-associated epilepsy?
- CHD2: chromatin remodeler important in opening chromatin so enzymes can access promoter
- Truncationsto CHD2 => less gene expression of genes that depend on CHD2 remodeling (haploinsufficiency)
What are the symptoms of Fragile X syndrome>
- Intellectual disability in males
- Characteristic facial featuers
- Joint laxity
- Behavioral problems: social anxiety and autism spectrum disorder
What is the genetic cause of Fragile X?
FMR1 = exon 1 of FMRP protein
- normal structure: promoter => 6-44 CGG repeats => FMR1
- fragile x structure: promoter => 200 CGG repeats => FMR1
- additional C’s = more methylation in promoter region = inhibition of transcription
What is the occurrence of congenital limb malformations?
1/500-1/1000 live births
What is a genetic cause of isolated congenital limb malformation?
- Deletion of a region including a TAD boundary => changed regulation of a gene in a neighboring TAD
How can epigenetic marks contribute to cancer?
- Hypermethylation of a tumor suppressor gene promoter => decreased expression
- Hypermethylation and deacetylation of a tumor suppressor gene => decreased expression
Can epigenetic modifications be inherited?
There is evidence traits can be inherited (Dutch Hunger Winter)
What can epigenetic therapies be used to treat?
- Kabuki (HDAC inhibitors)
- Epilepsy (HDAC inhibitors)
- Cancer (many targets)
