7: epigenetics in the heart Flashcards
what is SWI/SNF?
a family of chromatin remodelling complexes
same thing as BAF
what is Baf60c?
subunit of BAF chromatin remodelling complex, coordinates action of key cardiac TFs
needed for heart development
how would you know that Baf60c is essential for heart development?
when siRNA knockdown on Baf60c is used -> defect in embryonic heart morphogenesis (ventricular wall)
what are the mechanisms of action of SWI/SNF?
to remodel chromatin:
- repositioning (sliding) (predominant action)
- octamer ejection
- unwrapping
- dimer ejection
chromatin remodelling can lead to activation or repression
its context specific - depends on what is being recruited - activator or repressor
what is Brg1? why is it important?
- ATPase subunit of BAF complex: needed for cardiac morphogenesis, proliferation and differentiation
- Brg maintains myocardial cells in an embryonic state: interacts with other chromatin regulators (eg HDACs) to repress adult MHC (myosin heavy chain) and activate embryonic MHC)
- interacts with transcription factors - Brg1/Tbx mutation -> additive effect
what happens if Brg1 is removed? (on a molecular level)
disrupts cardiac morphogenesis, proliferation and differentiation
myocardial cells become highly differentiated
- adult MHC is upregulated (when it’s supposed to only be expressed in adulthood)
- embryonic MHC is downregulated
what is the relationship between Baf60c, Brg1 and TFs?
Baf60c promotes interaction between cardiac TFs and Brg1
facilitates TF binding to target loci
- in IP assay, shown interaction between Brg1 and TFs in the presence/absence of Baf60c
why is Brg1 a double edge sword
in adult cardiac hypertrophy, Brg1 is upregulated -> silences adult MHC and reactivates embryonic MHC
what is Mhrt?
Myheart is a lncRNA, overexpression restores cardiac function during cardiac hypertrophy
increased expression in adult heart
in cardiac hypertrophy -> Brg1 upregulated -> recruits HDACs -> represses Mhrt expression
what does Mhrt do?
exerts a cardioprotective effect by sequestering Brg1 -> prevents Brg1 from binding to chromatin targets
Brg1 helicase domain binds to chromatinized DNA instead of naked DNA
Mhrt competes with chromatin for binding to helicase domain of Brg1 -> displaces Brg1 from chromatin
what is Bvhrt?
lncRNA for cardiovascular lineage commitment
Bvhrt interacts with Suz12 (component of PRC2)
Bvhrt activates the cardiac gene expression from a poised bivalent state
