6: epigenetics in development Flashcards
what are polycomb group (PcG) proteins?
chromatin proteins that maintain a silenced gene expression state
what are trithorax group (TrxG) proteins?
chromatin proteins that maintain an active gene expression state
Hierarchy of cell potency
Totipotent stem cells: any + extra-embryonic cells
Pluripotent: all cell types but extra-embryonic cells
Multipotent: limited number of cell types in a particular lineage
what is the main function of PcG and TrxG proteins?
responsible for the maintenance of cell identity and contributes to the changes in transcriptional states in response to environmental/developmental cues
- need to maintain cell identity WITHIN and ACROSS cell divisions
- regulates developmental genes (HOX genes)
- expression patterns persist throughout life in the absence of TFs
- are antagonistic
what are HOX genes?
- a family of developmental control genes
- encodes for transcription factors that control the body plan
- expression pattern of TFs along body plan axis mirrors their collinear arrangement along their respective chromosomal location
what is PRC1 and PRC2?
polycomb repressive complex 1 and 2
is where PcG proteins are found in
what does PRC2 do?
contains EZH1 and EZH2 (predominant), which contain H3K27 methyltransferases
what does PRC1 do?
contains RING1A and RING1B, which are E3 ubiquitin ligases
what are the steps of the mechanism of polycomb-mediated gene silencing?
1: initiation/recruitment of PRC complexes
2: establishment of gene silencing
3: maintenance of gene silencing
4: reinforcement of gene silencing
5. inheritance of gene silencing
6: reversal of gene silencing if necessary
how is PcG mediated silencing initiated?
- recruited via unmethylated CpG islands
- accessory proteins bind to unmethylated CpG islands, recruits PcG - ncRNAs (eg HOTAIR)
- ncRNA binds to PcG -> guides it to specific region of genome
how is PcG mediated silencing established?
H3K27me2/3 mark by SET domain of EZH2/1 of PRC2
how is PcG mediated silencing maintained?
self-reinforcing silencing:
- EED in PRC2 recognises H3K27me3 and binds
- PRC2 undergoes conformational change
- EZH2 activity increases -> further methylates H3K27
how is PcG mediated silencing reinforced?
collaboration between PRC1 and PRC2:
CBX protein of PRC1 recognises H3K27me3 by PRC2 and binds
brings RING1A and RING1B to put ubiquitination mark
PRC1 and PRC2 can hold RNA Pol II at the promoter, preventing elongation and thus transcription
how is PcG mediated silencing inherited?
through semi-conservative DNA replication
DNMTs add methylation mark
- DNMT1 (maintenance DNMT): preferentially methylates the unmethylated strand of hemi-methylated CpG
- DNMT3A&B (de novo DNMT): has no preference, methylates both hemi-methylated and unmethylated CpG
EED can recognise old parental H3K27me3-bearing nucleosome, binds, adds methylation mark to the new neighbouring histones
how is PcG mediated silencing reversed?
using specific di-/tri demethylases
