Lecture 3 - Epigenetics Flashcards
Purpose of Epigenetics
-Expanding the capacity of the Genome to create diversity
What is Epigenetics
-study of Heritable mechanisms that alter gene expression which is not explained by DNA sequence
Epigenome?
-Between Genome and Phenotype
Major Mechanism
Transcriptional:
- > DNA Methylation
- > Chromatin Remodelling
Post Transcriptional:
- > miRNA
- > IncRNA
- > RNAi
Post Translational:
->Histone Modification (then affects transcriptional
DNA Methylation enzymes
- DNTM1: maintaince Methyltransferase
- DNTM3A + B : de novo methyltransferase -> highly expressed at embryo
How to make Hetereochromatin
- Methylation + Methyl-CpG-BP (recruiter) –> Silience DNA
- Histone Deacetylase + Remodelling Proteins –> hetereochromatin
Patterns of Methylation
CpG in Promotor -> methylation siliences gene
CpG Island shore -> Inhibition of transcription of gene
Gene Body -> normally methylated (role in optimal trans)
Repetitive Sequences -> inhibits trans of retroviral origin
Consequences of DNA Methylation
- Hypometh of Promotor -> Genome instability
- Hypermeth of Promotor -> siliences (TSG = CANCER)
- Deamination of 5-methycyt -> thymidine
- UV -> thymidine dimers
- binding site for carcinogens
Which Histone is mainly affected
-H3 is mainly affected:
> by adding to R-group of lysines of the N-terminal
Type of Histone Modification
> Acetylation - gene expression
Methyl - gene siliencing
Phospho: + mitosis + Meiosis
Histone Code Hypothesis
-different combinations of Histone modification, especially located near/in promotor may be very specific to the transcriptional state of that gene
RNAi
-RNA Interference
> Gene inactivation:
- both of specific genes + endogenous viruses/transposons/exogenous retrovirus
> directly interferes with mRNA coming out the nucleus going to get translated
Type of RNAi
siRNA:
- db: 21-23 NT with a TT3 overhang
- form complex with RISC and degrades the mRNA
miR
-20-23 NT long
act via:
1) Interact with 3’UTR of mRNA -> attenuates Translation
2) Lead to direct mRNA degradation
What do microRNA and siRNA need?
DICER
XIST
X-inacive-specific Transcript
- 17kb spliced non-coding RNA
- stable expression only in inactive X
- required to initiate siliencing
How is XIST formed
-X-inactivation begins when XIC locus synthesises -> XIST –> condenses chromosome whence it came from
Types of X-chromosome Inactivation
- Random: both normal + mutation product made
- Skewed: where 80% of pattern is domination by one of the Xs
-Fortunate Skewed:
> makes mostly normal product
-Unfortunate Skewed:
> makes mostly mutation product
X-inactivation and Autoimmune Risk
-skewed Inactivation in the Thymus during embryonic life –> most cells exposed to Father/Mother’s X –> after Parturition the T-cells recofnise cell sof the body with opposing X
Genomic Imprinting Definition
-non-equivalent expression of genes based on parent of origin
What is Genomic Imprinting
- for small portion of genes (<1%) -> Only one allelle is expressed the other is shut off
- which allelle is shut off is dictated by Parent-of-origin
- IGF2 -> allele is only expressed from father
Why is Genomic Imprinting a problem
-not usually a problem -> only if the expressed gene is mutated (Prader-willi and Angelman)
Cause of Prader-Willi Syndrome
- Maternal UPD
- Paternal deletion of 15q11-13
- Wrong imprting
Cause of Angelman syndrome
- Paternal UPD
- Maternal deletion 15q11-13
- wrong imprinting
- UBE3A mutation
