welcome to the everything epigenetics podcast where we discuss DNA regulation in the insights it can tell you about
your health I’m Hannah w and I’m the founder of everything epigenetics today my guest
is Dr Charles Breeze we touch on a lot of things regarding epigenetics of course but there are two main focuses of
our discussion today number one we describe the lack of diversity in these
epigenome wide associations studies or these Ewa studies we talk about those current challenges and how we can have
solution to those challenges and move toward a more representative data population the second thing we discuss
is several developed bioinformatic software tools that he has created called e eforge and Forge 2 these are
for the analysis of epigenome wide studies and genomewide Association studies as well a little bit of
background into my guest today Dr Charles joined the occupational and environmental epidemiology branch in
2020 as a post-doctoral fellow he received his PhD in computational epigenetics and genomics from University
College of London where he was an EU Marie cury predoctoral fellow and he’s
even worked for some other leading institutions including the University of Oxford the European bioinformatics
Institute and the alus institute for biomedical Sciences in Seattle
Washington this is where he actually LED an integrative analysis and generation of reference Mouse in code
data Dr Breeze has developed several bioinformatic softwares tools which include eforge and Forge 2 which I
mentioned will be uh part of our second half uh of the discussion we have today and now for my guest Dr Charles Breeze I
hope you enjoy welcome to the everything
epigenetics podcast Dr Breeze thank you so much for being here today thank you
for having me I’m excited to just hop right into it and really you know this is the first
time you and I have have ever really spoken over the phone I’m very familiar with your research but would love to just hear a little bit more about your
journey how you became really involved with epigenetics you know tell me everything about the epigenetics um and
yeah just kind of your your upbringing as well definitely so
um about the genomics or epigenetics um my first contact with um with genomics
was really when I was 16 so I was basically um you know a student
in high school and my father had um just gone off on a trip um to the north of
England where he had been discussing ancient history with some
archaeologists and one of them let my father a book on genomics uh which was
called genome by Matthew Whitley mhm um who’s uh yeah he’s he’s a very eminent
science writer and I just fell in love with genomics at the age of 16 I I read that book absolutely loved it um it had
all kinds of um all kinds of uh sort of different uh stories um each chapter was
a story about a specific Gene um and each chapter was also chromosome so it
had uh you know the the full set of chromosomes in the human genome and you
know it went through uh it took one example of a gene for every chapter and it focused for example on Hunting s
disease or on height or on you know uh BMI and it really focused on all these
different um very human aspects taking genes and individual genes as kind of
like an anchoring point and I absolutely loved it and from then on I knew I was
going to do research which would eventually lead to epigenetics um which is in my view very much part of
genomics but much more exciting because of the potential environmental aspect as
well yeah I wish I that’s a beautiful story first off I wish I had one that started you know that young it seems
like you really just ran with it you knew you were interested in it so I I
appreciate you you sharing that um and then talk to me a little bit more about your PhD in that journey I know you’ve
received received your PhD in computational epigenetics and genomics from University College of of London so
can you can you tell me a little bit about that um and maybe why you chose that particular pathway definitely so um
I was doing internships before the PHD just to get a good a good feel of what
research would be like um and I was doing this internship at at Oxford
University on uh mic rnas so you know these these very short rnas that that
have have many roles uh especially in in cancer but also in other conditions and
um I was just at that point I was getting really interested in epigenetics but of course some people consider you
know the whole RNA mic RNA world as part of like epigenetics and some people focus more on you know DNA methylation
and you know and histone modifications um so it’s kind of counterintuitive but I started from the micar um kind of like
research angle and um I was really interested in trying to understand how
environmental exposures can really you know eventually uh mediate all this
genetic risk right so um there’s long been a debate of you know nature versus
nurture right I mean is it is it something that we’re born with or is it something that we kind of acquire over
the lifetime and the real answer at least from Matthew Ridley’s book was
this is nature via nurt so we have genetic predispositions to some things
but then you know in our lives we eventually have a series of exposures
that can lead to a potential outcome and so it was this nature via nurture trying
to understand how this genetic aspect and this environmental aspect come
together that really led me to epigenetics to try to understand uh the answer to this problem yeah I I really
like that the nature Vian nurture I don’t think I’ve ever heard it be put that way I’m definitely going to start
using that now because that that makes sense hey we have these you know genetic variants or or you know the sequence we
get from Mom and Dad how are we able to affect those through the environment through these epigenomic changes so um
going to to start using that now set of verses I think that’s in that disting the distinguish um to distinguish both
of those in that way is very important and you know that’s great that you actually started out in the RNA the microrna modifications I think when we
think of epigenetics some people usually just think of the the DNA methylation or the hisone you know acetalation but the
RNA is still there and so very much important definitely and RNA modifications as well uh you know
chemical markers on top of RNA is also a really cool field absolutely and something that
definitely not my expertise so would love to hear about that more um but first want to really hop into your your
more epigenomic papers that we’re familiar with you know you do have one Dr Breeze that was published in 2021
this is actually titled epigenome wide Association study of kidney function identifies transethnic and ethnic
specific Loi what does that mean can you explain that to our our listeners and
what you did in that study definitely so um the the the study is the title is
long and complicated but the reality is quite simple so African-Americans are
actually three times more likely than European Americans to have kidney
failure and Hispanic or Latinos are actually 1.3 times more likely to have
kidney failure compared to European Americans and so this is a huge
disparity this is one of the biggest Health disparities out there and so what what we did with our study was to try to
understand using genom DNA methylation to try to really understand the
potential environmental and of course this genetic in to play behind this huge
Health disparity and we wanted to really find Target gen means that we can really sort of follow up uh to try to
eventually um have better preclinical models because um without that we can’t
really start addressing this disparity yeah and and what was the can
you talk a little bit more about exactly what you identified there um so you I’m assuming you looked at you know very
large population some African-Americans the um Hispanic and Latino population
compared to the Caucasian population so are you just looking um using the epigenome widest Association study to
look at those differences or you know how many positions did you find and what did that really I I would say all entail
definitely so uh we this is a two-tier design study so it has a large Discovery
um section uh there’s a large Discovery population but there’s also um a large
uh replication uh effort to really follow up and identify robust um
findings and so in our initial first study we analyzed uh
5,428 individuals so over a, African-Americans over a thousand European Americans and around 800
Hispanic Latinos in an initial scan to really identify um in the first pass
what DNA methylation positions are associated with kidney function and um
we identified um 93 cpgs that are actually uh
significantly um uh affected or sign they’re actually significantly associated with kidney function um so
this is the Discovery phase and so we conducted a replication study with over 8,000 individuals so an even larger
replication study um to really identify uh reliable results um essentially uh
that could overlap with the initial study so as we have uh two studies which are pointing to these sites and we found
we found that around 13 cpg GS um across different ethnic groups actually
replicated well and so these are key cpgs for followup to really try to
understand the fundamental biological Association of those cpgs with kidney
function um so yeah so this two study uh is actually uh the design the design
approach that we took yeah yeah know I think that’s a great design approach as well and I’m hoping my listeners know by
now why application is so important in in these types of studies um I had a really great episode with Karen suden on
that um from duke really talking about this hey if we find this Association we now need to validate it and replicate it
in several studies so um you have these these 13 cpgs in the second part of the
study that were replicated really well um and you’re then saying that those 13 cpgs are responsible for the difference
um that we see in those different um populations for for the kidney disease
so those the cpgs are kind of like um um a marker or a strong marker for U
important genes and Pathways that are associated with those differences um of course I want to caution that I mean we
did this is pro this is the largest uh ewas epigene Association study of kidney
function to date but we’re still early days in epigenetics and we still need to
increase sample size uh to really reach levels at which you can actually explain a large fraction of the variability
yeah um so yeah so we don’t these 13 cpgs don’t mean that we understand the
entirety of the difference but they’re a very good marker for Pathways which are underlying that difference absolutely
yeah that that’s great and I said kidney disease I meant kidney function um so I’m sure there’s going to be you know
this is really groundbreaking research if if anyone’s wanting to look into a function of kidneys of course or any
type of disease relationship to those kidneys these are the 13 cpgs that we would go to probably for that area of
interest is that a correct statement perfect I want to make this easy for for
our listeners to understand and see you know the the value of this uh research that you’ve you’ve performed now Dr
Breeze correct me if I’m wrong however um I believe you know after talking from a couple people from your team um in the
process of this study that we’re talking about when you performed it you really realized that the current analytical
tools using the ewos the epome wide Association studies are based on European data um which of course is not
going to be um really it’s not going to be an all-encompassing sample size that
you know for analyzing data from Latin and African populations so how did you come to that realization and uh what can
what can we do about it right so this is this is a a core issue in epigenetics
right now um this this lack of diversity in a lot of epigenome reference data so
um this is not just for ew but also for for gwz um which are the genome wide
Association studies uh which are some sort of the genomic the genetic equivalent of an ewas um but in whenever
we do an ewas or a gwas we always have this post ewas or post gwaz section
where we try to understand the fundamental biological Pathways and so
um we use a lot of reference epigenomic data to try to essentially map these things to genes to regulatory elements
and to uh underlying pathways and what we found was well we did this study um
across African-Americans and and you know european- Americans and Hispanics Latinos and um when we were trying to do
the post e section uh we really found that a lot of the reference mapping data
didn’t align very well with the African-American Or Hispanic Latino data
so we’re doing these pathway analyses and these integrative analyses and we’re finding that the European data Maps
really well with the kidney references but outside of Europeans it doesn’t really
work very well yeah so yeah so this was a huge this is a huge obstacle because it does it it’s not just an e problem
it’s also going to be a problem for G interpretation and actually for the whole of precision medicine so genome
epigenomic references are very important and getting those right is going to be a crucial step
forward yeah so I’m I’m curious why is this I feel like you hear about these issues all the time right the the
diversity and and the sample populations and even you know things like sample size and we can get into the some of the critiques of study designs here but why
is this the really the first time we’re saying okay this is an issue let’s do something about it you know um this led
to a lot of your recent work that was published last year in 2020 you reported a lack of diversity in the ewos which
we’ve been uh chatting about and then D methylation data so you know why are we just now now hearing about this I think
that that paper that you wrote is very very important definitely so um there’s been
um somewhat of a a a change of perspective in recent years um so a
couple of years ago there was a focus on trying to make uh GW more diverse people realized that GW data was not very
diverse um and what we really found last year was essentially um the same applies
to a lot of other Precision medicine especially ewas and epigenomics um the
the the individuals and samples that are taken are overwhelmingly European American and so um this isn’t really
including everyone and I mean research only really works for all of us if it includes all of us and that’s not what’s
happening right now yeah are there any other challenges um you would want to discuss for the
ewos and D methylation research in diverse populations um maybe some you
know other Solutions as as well definitely so um one of the one of the
key issues um that we found um is that often um the for example there are
specific genes that are known to be very well associated with um increased kidney
disease for example in uh certain populations so for example there is this Gene AP one and it’s associated with um
increased risk of kidney disease in African-Americans and so um while this
Gene is definitely um important to study
um there is relatively little um sort of epigenomic focus uh focus on
Technologies to really study that region of the genome and so we really need
targeted approaches we need approaches that are aware of the div the diversity
that exists in epigenomics and in human populations and technologies that really Embrace that and so we think that uh
obviously things that have been developed to date are um have been useful so far but we really want uh new
technologies and especially technologies that are targeted towards improving health and detecting uh associations in
regions that are critical uh for health conditions for example A1 and there’s a
number of other genes as well that you can list uh that would be critical to understand um diversity and disparities
in health yeah absolutely I know there’s you know a lot of work being done kind of in the um imprintome region area and
EP the genetics too with um in particular African-Americans and um you
know our Europeans because there’s going to be a difference for Alzheimer’s disease a very I would say um large
discrepancy so as we’re able to understand I think those differences across populations according to disease type we’ll be able to give a little bit
more information um now Dr Breeze you also proposed several solutions for this lack of diversity and I think these are
you know of course some some common solutions that um all sound great just need to put them into practice um but
these include things like getting people involved um getting people you know being able to volunteer for different
studies uh more data generation which I think is exactly what you were just hinting on um and then obviously some
cost-effective approaches such as Locus specific analysis and uh ancestry variable region analysis again which you
kind of uh touched on as well so um do you truly believe that we can kind of
move towards this more representation uh based you know studies or or you know do you still think that’s
a little bit far away how much how how much time are we going to take to put this into application and and move toward more a more representative data
sample that’s a good question so um we we defin we’re definitely in the first
steps of addressing some of that um there are some smaller studies which
which have been done um so far trying to understand uh diversity even in
epigenomics so for example topm which is this extraordinarily large uh study uh
focusing on Precision medicine has a subset of individuals and um subset of
participants which have been evaluated for DNA methylation and so there’s some really exciting work coming out of there
um I I think we we definitely need um studies that are that are targeted at
addressing uh we need Focus we need efforts which are focused on addressing this um disparity so focus on for
example increasing Hispanic uh samples increasing epigenomic analyses in Hispanics so uh targeted approaches in
technology but also targeted approaches in in terms of studies we need studies that really go after uh um trying to
solve the Gap um just doing more studies larger studies across everybody is it
sounds great but what we really need is also work in specific populations right work in Hispanics work in
African-Americans that’s really like focused on on increasing the numbers yeah I’m happy to to have this
conversation I think it’s something you know hopefully people hear us talking and say you know I don’t think anyone would ever disagree but I think that you
know getting the word out there actually talking about this will make people get more involved as well I’m really happy to say that with this podcast that I’ve
been doing now basically for a year I’ve talked to people with really amazing
backgrounds who are doing the studies themselves so um one comes to mind Dr yanita she’s actually out of Yale and
she’s Hispanic and she does you know all of these really nice EP genetic D methylation Hispanic based studies so
focusing on one different group and then being able to see those differences and compare them maybe from a larger population standpoint in in the future
um will only lead to you know helping this cause that in terms of needing more diverse uh sample type so I think it’s
it’s coming you know the future is bright I am excited um about it um and
then anything else you want to add there Dr Breeze regarding epigenetic work and and diversity we’re getting ready to
move on to our our second subject which I’m really excited to talk to you about too but any any last comments or
anything we can do better just as a community um with uh you know making these uh cohorts or ewas or jwas more
diverse uh definitely I think um also sort of essentially defending the value
of epigenetics research especially because uh Health disparities aren’t just a genetics problem we’ve talked
about AP1 but they’re also an environment problem and so for example
there huge issues uh for example in water quality and in other uh environmental exposures and conditions
um uh even within the United States between these different populations and so it would be extremely valuable I
think to to sort of um become more aware of that epigenomics is is is not just a
proxy for genetics but it’s also a proxy for for some environmental exposures and uh our real way to understand that
better is going to be by doing more epigenetics and by doing more work in that area yeah no thank you that that
was beautifully put I’m glad I asked if you had any other comments um yeah you know that’s great I think I I just got
you know I’m brand new to this world of epigenetics I don’t know what I don’t know we don’t know what we don’t know I’m learning as we go on this is a big
part of why I’m having this podcast is to talk to experts just like yourself in this amazing field that’s growing very
very quickly so of course um I’m really more familiar with epigenetics as it relates to aging and those biological
clocks and Longevity but um of course this is very very important work and um
you know I’ve just learned so much and and again really have only really knew have known the world of epigenetics
since three years and um you know the the research just continues to expand so um I’m excited to see definitely and I I
also want to um add you know why DNA methylation right so everybody who talks about epigenetics uh sort of there’s all
these different marks we’ve even talked about mic rnas and we’ve talked about hist modifications but DNA methylation
is there’s no there’s no um it’s not a surprise that DNA methylation has emerged as one of the major uh marks in
epigenetics and one of the reasons for this is that it changes with environmental exposures but is
relatively also has a certain stability throughout the lifetime and so for
example as you as you’ve discussed in previous podcasts it’s an extremely good marker for aging um but it’s also a very
good marker for smoking and other very long-term exposures um I can recall the
case of one participant in a study who um essentially uh we we stopped smoking
several years before and um subsequently uh when we evaluated the participant a
few years later this was five years later still had some signatures of the smoking Mark so even though he had
stopped smoking um you know there was actually um still a mark there an
epigenetic Mark right of of that exposure and so a little bit like
sort of a record of of all lifetime exposures DNA methylation is just an excellent
choice I’m so glad you said that I’m so glad you said that because uh I I will
say this I’m not going to name names but some of our researchers actually from Cornell that I work with very closely
through my work at true diagnostic um they actually came to visit our facility it was really nice we love you know
showing off our lab here in Lexington Kentucky um but uh we were basically talking to them and they said you know
what a lot of our friends they’re they’re uh disease experts uh but a lot of their
you know colleagues and friends have always been really writing on the fact that the transcriptome look to be the
best when studying infectious disease they’ve actually almost shifted entirely to epigenomics and DNA methylation as
that modification and I just think you know epigenomics the DNA methylation it
really does seem to be this underlying almost like um kind of gold mine for
understanding you know the how and not only the how but maybe the why eventually we definitely are starting to get the correlation causation we’ll see
what we can we can understand there um so I I really do I think DNA methylation acts as a great proxy to be able to
start and to study um I think what you said Dr Brees is really great because again when people think of epigenetics
they think of change and they think oh this changes really much but again DNA methylation is still stable enough to
have and hold on to that signature across the entire lifetime where we’re able to see what um we’ve been exposed
to so there’s there’s a lot of value there a lot of things that can be studied um all right Dr Breeze now
really excited uh to talk to you about a couple bioinformatics based software tools that you’ve created and developed
and you’re probably going to have to break this uh down a little bit more for us here now is it called is it do you
pronounce it e Forge in Forge to e Forge yes e Forge perfect so so this is you
know the analysis of epome wide Association studies ew and then those GW studies as well for that data so I know
you just expanded your Forge database so you know can you explain what this is
and um I’m definitely going to be sending this episode I I sent your work even to our our bioinformaticist at true
diagnostic because I just think this could be extremely helpful to people listening um of course our researchers
uh too definitely um so the names uh the frontation is correct uh efor was
actually named by uh the scientist who did the first uh human methylome that’s
Stefan Beck so it really goes back to yeah to a lot of DNA methylation work
but essentially what these methods are trying to do um they’re trying to essentially uh create robust
comprehensive and unbiased uh Frameworks for post ewas and post ewas analyses and
so um you often we do an an ew an epome wide Association study and um we come up
with with a list of genes well specifically a list of cpgs in the case of an e and um essentially once we’ve
done that uh study we have this list but we want to take that into sort into the
next step which is to identify fundamental Pathways biological Pathways which are associated and try to get some
biological insights into for example kidney function or the specific
condition that we’re studying and so um often What’s Done uh in the post ewse
analysis world is to try to uh do enrichment analyses and so um people
have all kinds of pipelines and different types of software to evaluate that and sometimes this is a bit ad hoc
so somebody just runs a couple of our scripts and comes up with some enrichment results and what we wanted to
do um was really create a sort of unified and robust framework for
conducting uh these enrichment analyses um and um it’s a little bit like Hing
cats there’s all there’s all these different different methods and we wanted to create some uh unified approach um
so so basically uh that’s that’s eforge and um it’s basically just um trying to
really come into the robust uh trying to come into a robust framework for
something that’s always been so uh you know um chaotic yeah yeah now now know
that that that definitely makes sense can you just Define what the enrichment analysis
means or or what that all pertains definitely so uh when you do a study um
you will often times um want to want to know what regulatory elements what genes
what enhancers um those those key sites those cpgs are coming up in and so um
for example you will do an ewas on on kidney function and you will find all these cpgs some of them are ingenic
right so we don’t know what they do um some of them maybe in a promoter of a gene so you have a slightly better idea
but um to really understand this at a systems level um we need to take U an
approach that’s called inter integrative epigenomics so taking uh epigenome reference data and trying to integrate
that with the results from your study to try to see um what what key enhancer
components what key tissue components what cell types are really associated with your results so for example in the
case of a kidney function study uh you can do integrative epigenomics to try to find out you know is it the
nefron that’s really coming up what pathway inside the Nephron in the kidney uh is really the important pathway and
so this is all an effort to try to um link this to fundamental biology and try
to understand the fundamental biology behind uh your epigenomic results and so
uh that’s what efor is really been all about it’s really been about uh doing integration and doing it in a robust way
so um eforge always analyzes uh the whole set of tissues in a human body and so
sometimes uh you know when people do post post EAS analyses they only analyze
you know some t- cells and you know and some some B cells and they come up with a result but how does that look across
the entire set of cell types that’s what we want to know so it’s all about robust
and comprehensive Frameworks uh to really come up with reproducible results yeah yeah that that’s great again I
if I could go back to school I would definitely do some bioinformatics works or like some computer science um I’m I’m
more you know General General biology based in genetics so um I guess to to
understand this is would this be correct Dr Breeze you you know you have all of this data after an Ewa study there’s a
lot of different normalization Pathways and pipelines and you know it’s messy
it’s not necessarily regulated Here Comes e Forge you’re putting in all of that data and then that’s going to tell
you kind of again it’s going to normalize I guess a lot of that information and then maybe even tell you
um yeah more of like the how the mechanism of action how can we make this applicable and and take it out to our
true biology and and um yeah related to our fun fundamental understanding is that correct maybe definitely definitely
and um I would also add that uh one of the focuses of eforge is um so
essentially what we’re trying to do here is um not just find the underlying Pathways
but also correct for all these different sources of bias so eforge under the hood has different uh methods for bias
correction uh just to make sure this this is all done properly and you’re not getting spirous results so yeah so
definitely that’s that’s a good summary well that that’s great is this open source for anyone to use are there there
any costs involved open source open source and all of the versions are publicly listed on multiple databases uh
GitHub um Zeno we have all kinds of backups because we want to keep this open source
for the community yeah how do you create this I imagine it took a very long
time it did um I yeah it was interesting because uh actually my background I
actually started uh in the wet lab and so when I was doing my Curr work at Oxford I was 100% wet lab and um it was
interesting I started getting more into computational biology and uh really sort of um learning more about uh programming
over the years and uh essentially during the PHD that’s when I really worked on
uh creating e Forge and yes it did take a long time but it was definitely worth it yeah yeah well I think I think it’s a
beautiful tool and and what I’m going to see um if if we can play with a little bit um so just to confirm as well the E
Forge is to better understand the ew and then the forge 2 is to better understand the GW is that correct definitely and of
course e are very different from G so Forge 2 is actually really different from eforge like in many of its
underlying assumptions um but uh the the key result is is the key objective is to
unify to create a unified framework to really um do these analyses properly and
um definitely so we can translate the value from all all all the value that’s um coming from the study to eventually
translate that into preclinical models and into work that can eventually lead to um uh essentially results for people
who are uh taxpayers who are funding all of this work perfect and you kind of hinted at
this as well Dr breed when you were talking about the Ewa study um this is a reoccurring theme on my podcast so
listeners if you’re you’re tired of hearing about it I’m sorry but this is very very important um what about the
cell type spec specificity um you said you know if you’re you have an eball
study and you’re trying to again find the pathway what’s happening in the body they may be only looking at one certain
cell type so what you can even redefine it for listeners Maybe Who who are just now you know listening to the podcast
and are new but yeah what is cell type specificity and and why does it matter when we’re we’re using you know eforge
or Ewa studies definitely so cell type specificity matters for almost all areas
of epigenetics um you’ve probably mentioned epigenetics of Aging um so in
epigenetics of Aging as you know you have um you have extrinsic epigenetic
age acceleration and intrinsic epigenetic age acceleration and that extr or intrinsic is whether the changes
happen within the cell or because of changes in cell composition and so um
this is critical to understand aging it’s also critical to understand uh every us that’s ever been done is
critically dependent on cell composition so um as you know this was a bit of a scandal at the very beginning of e but
uh very first e we’re trying to find uh results um in Blood and of course blood
has B cells it te- cells there’s many different cell types and uh you know
what people found essentially Houseman uh and several other researches what they found was that you have to really
correct for these cell type uh proportions because they can drive your entire study results and thankfully that
was that was found very early on and uh subsequently every single Lew that’s been done uh has uh adjusted for cell
type proportions or at least there’s been a focus in the field to adjust for cell type proportions um to really make
sure that your results are driven by changes in DNA methylation that are happening uh you know inside inside each
cell and so um essentially cell type specificity is crucial for e is crucial
for aging and uh it’s really also crucial for understanding the
fundamental biology so when we do these post EAS analyses um we really want to
know which cell type these enhancers are active in uh that that are overlapping these sites from our study
and you know really trying to map um at a cell type level so we can translate
this to Precision medicine so for example in the case of kidney function which cell type in the kidney is the one
that’s really driving all of this change and how can we know more about the pathways that are happening there so
trying to understand biology I mean I come from the wet lab I really love biology and trying to understand the
fundamental take message that’s critical for me yeah know I can definitely tell I
mean your passion is is seeping through as as you’re talking so I can I can definitely see it there and you know
that’s always extremely nice to to know your your life work and everything something you’re really passionate about
um and you feel very very strongly for so yes cell type specificity is absolutely crucial and you made a good
point good thing we found out now could you imagine if we release all of these studies and then decades later you know
everything we’ve ever known I mean I I just couldn’t imagine so so yes that is um I think think something I I struggle
with every day when I talk to you know Healthcare Providers or researchers and and some people aren’t even informed about this and I think it’s really
important when we’re looking at at epigenetics even more for the Aging aspect especially when people are starting to use some of these clocks for
more of a a commercial aspect so um Dr Bree you’ve actually brought up uh you know epigenetics and how it relates to
aging well I I’ve brought it up I think and and have pushed it on you and asked you about it but are are you very
familiar then with the epigenetics and aging I just have to ask because the audience is I’m sure very interested in that as well um or do you ever plan on
doing any work in that space definitely so I’ve collaborated with Steve Hova on several studies and actually um there is
a specific version of eforge which was developed for one of his aging studies so there’s definitely a lot of focus on
on uh aging and its relationship with multiple human uh conditions for example
aging and cancer is a huge field um so yeah I’ve definitely worked
um on uh aging work um the the the fascinating thing and one of the really
open questions for aging is uh fundamentally how does the epigenetic clock really work and so uh Steve hova’s
clock which as you know was developed published in 2013 uh came up right around when I was
doing my PhD um you know it’s an extremely uh precise biomarker of of
Aging but nobody really understands at a fundamental level how it works and so um
we we actually team together to do more eforge analyses on on uh the epigenetic
clock um and what we found was there’s uh some uh strong associations for
example with the repressive polycom complex but um that needs to be followed
up so there needs to be more work done uh to understand the fundamental biology of aging and what’s driving what’s
making the epigenetic clock take well we don’t know that but we’re trying to find out more yeah yeah I I’m going to when
when we stop talking online I’m going to talk to you offline about some some opportunities that that I just thought
of but yeah you know what what would be interesting Dr Bree is Dr Morgan LaVine came out with a really nice paper where she creates these like cpg I think she
calls them modules where she Compares all of the really famous and I would say the you know the best of the best the
most precise sensitive accurate epigenetic clocks that have been created to date and then she creates uh the
overlap of these modules in terms of the cpg so it would be really I think
interesting if you were to take those cpgs that overlapped in specific clocks and actually ran them through that your
your e Forge to see all right where are they overlapping in terms of again the functionality right the mechanism of
action there so I think that’s just one of the many ways we can start to to put your uh really nice bioinformatic
software tools to to use definitely yeah
yeah go ahead no I was also going to say uh of course for aging we’ve also people have also tried to do GW to try to
understand the clock so trying to go back to genomics and trying to understand DNA methylation changes and
uh there’s definitely um also applicability for Forge 2 there so I mean these methods are obviously um
going to be very useful going forward and um yeah and that’s definitely a good idea that you mentioned there yeah yeah
absolutely no excited for what’s to come now I I should have asked this uh at the beginning of the call I should say but
why kidneys why why how did you get started there good point um so one of
the yeah so one of the major areas where the environment uh really um ends up
affecting uh overall health um is uh is
through for example through water so we all know that there’s substantial exposures to to lead and to to other uh
toxins um and some of these especially for example for pasas which is this group of you know um organic compounds
which are found to be in the water um in certain parts of the United States um all of these uh different uh all these
different exposures often times they they reach people through water and it’s the kidneys that really filter um not
just the blood but they act as a filter for a lot of toxins and so um this was really one of the most exciting areas I
think to do uh epigenetics in so um obviously there’s other organs which are crucial the liver is crucial um for for
exposure to toxins and uh there’s there’s there’s a number of other approaches that one can take
but to understand Kidney Health that’s tightly linked to health disparities as I said before um there is a
substantially higher likelihood of of kidney failure outside of european- Americans so try to understand to try to
understand Health disparities we really have to focus on the kidney yeah know I appreciate that that
insight there that definitely makes sense and makes for a good you know organ to study and uh you know hopefully
we can figure out why those Health disparities are are happening through that that you know kidney function and
filtration system so to speak so we’re getting toward the end here Dr Breeze just a couple couple questions left for
you that I want to PR pick your brain about um what’s next you know what are you most excited about what are you
working on is it uh some of these more D diverse you know inclusion type of uh
populationbased studies are you focusing on a certain um population are you working more on any of these E4 or or
Forge 2 what’s next for you definitely so um I’m glad you mentioned the kidneys
because our next study is going to be on kidney cancer to try to really understand um how that how diversity
affects kidney cancer and DNA methylations so that’s going to be uh our next big effort I’m really excited
to do more work on that uh and we’re trying to get that done as soon as possible um because all these
epigenetics results can’t wait um and the the next big project apart from um
apart from that um apart from the focus on kidney cancer uh of course what we’re trying to do is also expand uh the
pathway approaches so you can do pathway analyses um taking data from eforge and feeding that into pathway analyses but
uh what we really want is to integrate the epigenetics and the pathway software together very closely so we can really
uh map Pathways in individual cell types that are essentially linked to study results so we’re trying to bring uh the
wet lab mentality and uh computational biology really close together uh so we
can get more information on the fundamental biology which I think is the most exciting part of any study yeah
yeah I mean I couldn’t yeah I couldn’t agree more with that well um I’m really excited for that study to understand you
know again the the kidney functionality and the cancer and and how that all ties back into the genomic profile the
epigenomic profile and then how we can hopefully make that an an application for for users too so um Dr Breeze one
last question on the end of the podcast I usually ask everyone all of my guests if you could be any animal in the world
what would you be and why that’s a very good question um it’s not on the agenda
that I said beforehand so um that’s pretty funny so my wife she has these rabbits so I’d
probably want to be one of them actually because they get the very best life they get treats they get all kinds of snacks
I mean I you know sometimes I think my quality of life is actually kind of like on pass so like if I was going to keep
you know my quality of life going I’d probably be one of those rabbits yeah oh very good how many rabbits do you have
you said just two there’s two and they’re actually yeah they’re actually um they’re actually resting so yeah
that’s that’s what they’re up to yeah well good sounds sounds like a really good life well you know Dr Breeze uh
we’ve come to the end of this amazing podcast interview for any listeners who want to connect with you any bioinformaticist or research who want to
get access to the eforge you know where can they find you where can they get these tools definitely so I’m always on
Twitter and I’m also um really involved on GitHub so uh if they can reach out on
uh either one of these uh social media uh or computational U um web pages uh
I’m also definitely uh so the latest release of Forge DB by the way uh that’s
that’s all public so all of these web pages are are are linked um and uh yeah
and I’m also available by email so I would love to chat about that perfect and I’ll make sure when I I
publish this on my website that I put all the links that way people can you know go to your profile and uh you can
get that exposure and and people can contact you as well so thank you everyone for joining us at the everything epigenetics podcast and
remember you have control over your epigenetics so tune in next time to learn more thanks Dr Breeze thank you very much
