Aaron Viny Profile picture
Sep 5, 2019 15 tweets 6 min read Read on X
Very excited to share my work on Stag2, chromatin architecture, and effects on hematopoiesis! Join me in a @MedTweetorials of why this is so important! @CellStemCell cell.com/cell-stem-cell…
The cohesin complex is comprised of structural proteins (Smc1a, Smc3, Rad21) bound to a Stag protein. We and others have described that alterations of each affect hematopoietic self-renewal and differentiation.
However, both the mechanism and the biologic reason for the overwhelming prevalence of STAG2 being overwhelmingly the most commonly mutated component in cancer was still not known.
How does the cohesin complex affect 3-dimensional DNA structure and how does this affect transcriptional regulation? What is the difference between loss of a structural cohesin versus a Stag protein?
Using novel conditional KO mice (now available @jacksonlab), we show major hematologic defects (myeloid skew, B cell loss) with Stag2 loss, but not in Stag1. Co-deletion is lethal (shown by @johannes_zuber and colleagues); Stag1 redundancy must maintain viability, but how?
ChIPseq for Stag2 and Stag1 in HSPC of WT and Stag2 KO mice shows both common and Stag2-unique binding sites with Stag1 able to bind TAD boundaries. If Stag1 rescue maintains TAD integrity, is structural integrity lost where Stag1 fails to bind?
Genes with decreased expression and decreased ATAC accessibility lose short range DNA-DNA interactions by HiC (10kB resolution), including key B cell lineage commitment genes, including PU.1 programs. Is this a loss of PU.1 expression or a loss of activity?
PU.1 expression is preserved in MPP and CLP populations, but ChIPseq for PU.1 shows decreased PU.1 binding genome wide. But does failed expression impair DNA structure or does DNA structural changes impair transcriptional programming?
The PU.1-target, Ebf1, loses insulation, accessibility, and expression. As PU.1 is a putative pioneer factor, it has the capacity to remodel chromatin. We overexpressed this key master transcription factor but were unable to restore Ebf1 expression.
This illustrates that changes in local interactions are in fact the cause of abnormal gene expression as expression of PU.1, an upstream transcription factor cannot rescue the altered chromatin architecture or restore target gene expression.
Addback of Ebf1 cDNA rescues lymphoid lineage commitment and B cell colony formation in vitro and in vivo.
Hematopoietic differentiation requires dynamic 3-dimensional change. It is this very functionality which we investigate, going from locus specific loop-alterations to decreased accessibility, decreased expression, and finally to an observed defect in hematopoiesis
In this setting the pioneer factor PU.1 was unable to open chromatin at target sites in the absence of Stag2, however, B cell development/differentiation could be rescued through restoration of a downstream target gene beyond the choke point.
Many thanks to @rosslevinemd the best mentor in the biz and amazing colleagues @bowman_rl @vp_lavallee @dana_peer @job_dekker @dekker_lab and @RossLevineLab COMING SOON: The Viny Lab. Stay tuned! @cohesinlab
A huge debt of gratitude to @DamonRunyon @EdwardPEvansFdn and @theNCI for career development support—the war on cancer couldn’t have better allies! Also please welcome #EvansMDS to the #twitterverse! Follow them at @EdwardPEvansFdn

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More from @TheDoctorIsVin

Oct 4, 2020
Almost exactly 17 years ago to the day, fresh off my 100 days post-bone marrow transplant for acute lymphoblastic leukemia, I had a visit from Aly Friedman. My flirting was pathetic, but endearing enough that we started dating. We’ve now been married over 12 years. #yourvelocity
And today, as part of the virtual @velocity_ride, our 5 year-old daughter wanted in on the fun! #yourvelocity
So today, I’ll be teaching her to ride a 2-wheel bike! Follow along and cheer her on! And donate to team “May the @DrGarySchwartz be with you” and to the amazing cancer research at @columbiacancer and donate at velocityride.org/index.cfm?fuse…
Read 16 tweets
Sep 10, 2020
This is my last week at @sloan_kettering after 8 1/2 years. No one had as much impact as @rosslevinemd, and so with my final MSK tweetorial before @cohesinlab moves to @columbiacancer to start @cohesinlab, a few of my favorite memories and pearls of wisdom from @rosslevinemd 1/25
In 2016 during the Vice President’s @CancerMoonshot initiative, there was a planned visit for @JoeBiden to come to @sloan_kettering. I heard the original plan was to visit the @CharlesSawyers lab, but Secret Service preferred the RRL building. 2/25
@rosslevinemd met and spoke with VP @JoeBiden then led him through each laboratory bay where a handful of us were waiting to tell him about our work with a “cooking-show” style setup ready. My station was a western blot (an old, super unsexy protein quantification assay). 3/25
Read 25 tweets
Jul 29, 2020
The Viny lab @cohesinlab is looking for motivated and courageous postdoctoral scientists to join our small but mighty group. @cohesinlab will open next month at @ColumbiaMed @columbiacancer & @CSCIColumbia (1/15)
We will focus on employing new and existing mouse models, primary patient samples, and state-of-the-art epigenomic/transcriptional assays for assessing 3-dimensional chromatin structure in the malignant context. These are the core principles by which we will operate: (2/15)
1. We are and will always be focused on improving the lives of the patients afflicted with cancer. Yes, we will work hard to secure grants and papers but those are simply the means to achieve our primary mission (3/15)
Read 15 tweets
Jul 1, 2020
1/ Sometimes coincidence makes you take a beat. Today is day +6,209 (17 years) since my allogeneic bone marrow transplant for relapsed Acute Lymphoblastic Leukemia. Today I am rounding as the inpatient leukemia attending. I brought cake.
2/ And I’ve tweeted my annual transplant anniversary before—worthy of much celebration—but this year is different. Even different from my 10 years cancer free as a @sloan_kettering fellow on the BMT service.
3/ Because this year, while I celebrate on service, it’s also my last week as an attending physician at MSK.
Read 17 tweets
Jun 6, 2020
1/ I’ve been thinking about this pledge and how best to take steps towards fighting systemic racism—while I don’t yet have a lab, like @SantoshVardhana I want to identify tangible actionable ways to make a difference. He and @leowanglab and @juliamaxson inspire me to plan now
2/ I pledge to bring in a URM high school or undergraduate for a paid summer internship who might not orherwise get #STEM exposure and then avail myself and my #WhitePrivilege to help mentor/navigate the system
3/ I pledge to seek out schools with less access to science education and commit to listen to what the teachers think the students need and provide education and time to address these areas
Read 4 tweets
Apr 12, 2020
1/n Today is day 28 away from wife and daughter. The first half of this separation was spent as leukemia attending @sloan_kettering for both #COVID19 and non-COVID hospitalized patients before cohorting strategies began and while guidelines for stewardship of #PPE were in flux
2/ We continued to give world class care to our patients, but that meant high risk exposures to my team and myself. Friends and colleagues with cough or other concerning symptoms were sent immediately for testing thanks to the amazing laboratory medicine dept efforts by @EBabady
3/ Many healthcare workers were found to be positive and went home with a range of disease severity and symptomatology. One thing was clear--our exposure risks were just as much from each other as from the patients. #HeroesOfCovid19
Read 21 tweets

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