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Genetics and Arrhythmias: Beyond Mendel's Peas
The Influence of Epigenetics on Electrophysiologic ...
The Influence of Epigenetics on Electrophysiologic Disease (Presenter: Andras Bratincsak, MBA, MD, PhD)
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I'd like to invite our next speaker. It's Dr. Andras Brastynchak, who comes to us from the University of Hawaii and is going to talk to us about the influence of epigenetics in electrophysiologic disease. I'd like to thank the organizers for inviting me to talk about the epigenetics of cardiac disease. I hope this will start. There we go. I think this is a fascinating topic that I dove into first three years ago in a SADS meeting. And at that time, when I prepared for my talk, it really felt like, oh, this is something else. I don't know if I can give this again. We're going to hear the talk again now. Yeah. It might be a little difficult. Here, let's try this one. So it felt like jumping down the rabbit hole. This is a brand new word with a different language that you might have forgotten since medical school. But it's exciting and fascinating. I believe the next century we will hear, the next decade we'll hear a lot more about epigenetics and how it influences the electrophysiologic diseases. So I would like to give you, I don't have any disclosure, but the disclaimer I have is that this is a vast topic. You can probably fill an entire conference or an entire session with this. I'll try to condense this in the next 10 minutes and invite you to jump in with me in Alice's wonderland of epigenetics. So let's start with the genome. We have about 20,000 genes that encode for protein in our genome that can create 100,000 RNA transcripts. And it can produce more than a million different proteins. So this generates a protein complexity that is 40-fold what is encoded in our genes. So how do you generate this amount of protein complexity? It's easy to say, epigenetics. So what is epigenetics? It's the summation of all kind of processes that is involved in the generation of a functional protein from your encoded genes. And it involves several things, gene accessibility, transcription modifiers, alternative splicing, gene-to-gene interaction that is called epistasis, post-translational modification of protein, just like phosphorylation. And you have another 200 agents that can change a protein function, protein folding, trafficking that can be involved, and also very complicated multi-gene interaction that can be observed in different ethnicity and gender. All this together gives rise to an enormous phenotypic plasticity given the same genetic background. So imagine it's like an architectural plan of your house that you have it as a genetic code. And then house, you can be in 40 different ways depending on what kind of appliances you choose, what is the color of the wall, what kind of wood you have. That's epigenetics onto the genetic code. Doesn't only explain phenotypic plasticity. I believe it also opens the door to all kinds of therapeutic possibilities that I would like to show you. So the first example is in Long QT syndrome, phenotypic plasticity in Long QT syndrome. We all know that Long QT syndrome has a diverse phenotype. There is a family here with the same case Q1 mutation. And two siblings with the EKGs can see that the T wave morphology is different and a QT is longer in one of them than the other. So also know that there are a lot of different things that can affect how a mutation manifests. But the manifested QT interval is the most important because the phenotype matters. It has prognostic and therapeutic implications. So here I would like to show you an epigenetic mechanism, how this QT phenotype can be affected given case Q1 mutation. So here is a case Q1 gene. The gray area is the protein coding region. And afterwards, where you see there was red lines, that's non-coding, the three prime untranslated region of the gene. And you can see variations, polymorphisms there, which is called single nucleotide polymorphism or SNPs in the region which can bind protein or some RNA. So Crotty's lab found this polymorphism and they demonstrated that if you have the polymorphism present on that three prime untranslated region, it silences the gene. So in a heterozygous mutation, which most of the families have, you have the mutant gene and the normal allele. If these polymorphisms are present at the end of the mutant gene, the mutant gene is silenced. So you generate normal RNA transcripts and you produce a normal protein while if these SNPs are present on the normal allele, you silence the normal allele. And because of that, you have dysfunctional protein or mutant RNA production and dysfunctional protein synthesis. This observation is true in a phenotype with the reduced RNA synthesis. So if you have the normal allele here, which has the SNPs on, the normal allele is silenced. So you have reduced RNA synthesis from normal allele, you have decreased amount of normal protein production, and with that, you have a significantly prolonged QT. There is another epigenetic mechanism that can influence the expression of genes, which is genomic imprinting. In a somatic diploid cell, you have two alleles, one from the mother, one from the father. For nothing better, it's called petrigene and metrigene. If you come up with a different name, let me know because it sounds like petri-dish and metri-dish. This differential silencing of the alleles is regulated by DNA methylation and methylation or acetylation of the histones. Whenever that is present, it silences that very allele in the gene expression from the allele. KCNQ1 is known to have tissue-specific genomic imprinting. It usually is the metrigene that is expressed in all kinds of tissues, but in the heart, there is bi-allelic expression of the KCNQ1 gene. However, this is not 50-50%. So, it's not 50% coming from the mother and 50% of the father. There are several things that affect genomic imprinting, which is actually in the centromere of the chromosome and usually is inherited, the pattern is inherited from the mother. So, genomic imprinting can also modify how much you are expressed from your maternal gene or paternal gene, and that can change the phenotype. Not in Long QT syndrome, but in a mouse model of Prader-Willi syndrome, they were able to modify genomic imprinting to the extent to rescue the phenotype. And again, a little bit farther, in maize, they were able to control gene expression by modifying a genomic imprinting differential on the allele. So, this begs the question, if you have a KCNQ1 mutation in a paternal allele, are you able to, allele-specifically, depress or suppress the mRNA transcription by modifying genetic imprinting, methylation of the DNA, histone modification, or developing RNA that can suppress the RNA synthesis from the mutant allele, therefore decrease the amount of defective protein synthesis, shorten the QTc, and potentially rescue the phenotype? My second story brings us to alternative splicing in Brugada syndrome. So, alternative splicing is the assembly of RNA, mRNA, from different building blocks of the DNA, different exons on exon parts, and this obviously results in different protein structure and protein function. 90% of human genes have alternative splicing present, and then the different splice variants are usually expressed at the same time. The sodium channel that is encoded by the SCM5A gene has nine splice variants in exon six, and in us, most of the adults, the canonical form is expressed and abundant. However, there is a fetal exon form, a fetal splice variant that has a seven-amino acid difference in the voltage-sensing domain of the protein. So, if you look at here, here's the seven-amino acid difference in the voltage-sensing domain. It's not difficult to imagine that this has different properties. It has a slower activation and deactivation, which results in a decreased peak and overall current and strength of the depolarization. Interestingly, this results in a different phenotype. Similar to a mutation in the sodium channel gene, this results in a loss of function. I don't know what happened with my fonts, and results in an arrhythmia and conduction problems in the patient. They also found that if these fetal splice variants are abundant in patients, it can result in Brugada syndrome and potential sudden cardiac death, as you can see with these EKG inserts. These are genetic negative patients with a phenotype of Brugada syndrome that can be explained by alternative splicing. Even more interestingly, you can silence the splice variant, or you can force, with the blocking of a splice variant, you can force the other splice variant to be expressed. So, again, there is a potential mechanism how you can rescue the phenotype. If I had some more time, I would explain to you how Mario Del Mar's group created the mice of placofilin conditional knockout, where the placofilin heterozygous mutation led to a decreased expression of all kinds of genes, among which there is the ryanodine receptor gene, which creates a different calcium homostasis and leads to an arrhythmia before the morphologic presence of armitage cardiomyopathy, very similar to what we see in humans. But I don't have the time to have more of this. So, Silvia Priori bumped Mario Del Mar. This is Dr. Priori's group, who presented a very elegant mechanism how to rescue a phenotype. You know that CPVT is caused mostly by a ryanodine receptor mutation, which results in a pathognomic arrhythmia of bidirectional ventricular tachycardia. And in Dr. Priori's group, they screened a lot of small RNAs, small interfering RNAs called siRNAs, and they found one among thousands of targets that specifically adhered to the heterozygous mutant allele, and they were able to silence the expression from that mutant allele. With that, they showed that, compared to the heterozygous control mouse, they decreased the expression of RNA from that model. And with that, the protein synthesis was also decreased. Most importantly, they showed that they were able to completely abolish ventricular tachycardia in that model with the gene-specific, allele-specific silencing. So, in summary, epigenetic modification can explain phenotypic diversity and plasticity, so you may think that the Cheshire cat is actually a house cat or a street cat with alternative splicing. I think you have to consider, I have to think outside the blocks. If you need to connect the dots, you may need to think about whole-genome sequencing, and I say this very cautiously because it opens a Pandora's box if you don't know what you are dealing with. And I think that epigenetic mechanisms may offer powerful therapeutic targets to rescue a disease phenotype. I would like to finish with this Alice in Wonderland quote. You know what the issue is with this world. Everyone wants a magical solution to their problem, but everyone refuses to believe in magic. Thank you very much. Thank you.
Video Summary
Dr. Andras Brastynchak from the University of Hawaii discusses the influence of epigenetics in electrophysiological diseases, specifically focusing on Long QT Syndrome and Brugada Syndrome. Epigenetics refers to the processes involved in the generation of functional proteins from encoded genes, including gene accessibility, transcription modifiers, alternative splicing, and post-translational modifications. Dr. Brastynchak explains how epigenetic mechanisms can affect the expression of certain genes and the phenotypic plasticity observed in these diseases. He also highlights the potential therapeutic possibilities that epigenetics offers in rescuing disease phenotypes.
Meta Tag
Lecture ID
6686
Location
Room 203
Presenter
Andras Bratincsak, MBA, MD, PhD
Role
Invited Speaker
Session Date and Time
May 09, 2019 10:30 AM - 12:00 PM
Session Number
S-013
Keywords
epigenetics
electrophysiological diseases
Long QT Syndrome
Brugada Syndrome
therapeutic possibilities
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