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The human body runs on one genome—but every cell reads it differently. How?
To find out, we need to measure both gene expression and chromatin accessibility in the same nucleus.
So we did, across 21 adult tissues and nearly half a million nuclei. 🧵
🔗 www.biorxiv.org/content/10.6...
Thank you Broad Institute of MIT and Harvard for this profile. The last 2 years have been an extraordinary moment of creativity and inspiration.
If you’re interested in joining us, PM me! We’re building new methods, models and ML tools - we’re recruiting at all levels!
Shaped by a tumultuous childhood, Broad researcher and epigenomic tool-maker @jbuenrostro.bsky.social pivots to studying the biology of stress and adversity and finding new ways to boost resilience.
We then engineered this interaction: we synthetically tethered RUNX2 and KLF2, forcing their collaboration to create a stronger and more specific gene expression response.
We’re excited about this direction. Synthetic TF tethering may provide a general approach for engineering gene expression in cells, and a path toward more programmable control of cell identity.
I’ll again thank @igvfconsortium.bsky.social and team. Please reach out with feedback.
Fast forwarding through a lot of work: we screened ~3,500 TFs, profiled ~750K cells with perturb-SHARE-seq, and identified KLF2 as a potent context-specific repressor of exhaustion programs.
These same programs are associated with favorable outcomes in CAR T therapy, motivating us to dig deeper.
We next asked: how does KLF2 work?
Using perturb-SHARE-seq, we applied seq2PRINT and found that RUNX TFs are highly collaborative, enabling cells to access diverse regulatory programs. Additional experiments revealed that RUNX2 and KLF2 physically interact to regulate key exhaustion genes. 🧬
Many regulators of T cell exhaustion have been discovered. As our community saturates discovery of endogenous regulators, we reasoned there may be major opportunities to combine perturbations and/or design synthetic proteins.
We hypothesized that combinations of TFs are required to reprogram T cell identity. This is motivated by the observation that most cell reprogramming strategies require multiple factors.
We therefore set out to identify TFs that collaborate within exhaustion-specific programs.
My group has long used epigenomics to define cell types. Since joining @harvard.edu SCRB, we set out to create strategies to engineer cell fate and state.
Here, we look to engineer CD8 T cells, where exhaustion limits their broader therapeutic use.
A little late to Bluesky but my postdoc work w/ @jbuenrostro.bsky.social now out in @nature.com
"Epigenetic memory of colitis promotes tumour growth"
www.nature.com/articles/s41...
We wanted to understand how transient inflammation can create an increase in cancer risk, even after full recovery 🧵
It’s well known that inflammation increases cancer risk, but how?
The answer: the epigenome "remembers" inflammation and primes stem cells for cancer.
Here is our paper: nature.com/articles/s41...
And a special shoutout to the lead author
@snaga13.bsky.social
A 🧵
This reframes how we think about cancer.
It is not just about having the right mutation in the right cell type. It is also about a cell's prior experiences.
In short, a cell’s history, written into its epigenome, can shape how disease unfolds.
It’s well known that inflammation increases cancer risk, but how?
The answer: the epigenome "remembers" inflammation and primes stem cells for cancer.
Here is our paper: nature.com/articles/s41...
And a special shoutout to the lead author
@snaga13.bsky.social
A 🧵
It’s well known that inflammation increases cancer risk, but how?
The answer: the epigenome "remembers" inflammation and primes stem cells for cancer.
Here is our paper: nature.com/articles/s41...
And a special shoutout to the lead author
@snaga13.bsky.social
A 🧵
The answer was yes! Using a new method (SHARE-TRACE), we found that inflammation rewires the epigenome of stem cells that persists long after recovery.
These changes are clonal, encoded through TF activity, and stabilized over time by DNA methylation, forming a durable molecular memory.
We then introduced an oncogenic mutation.
What we saw was striking: cells with prior inflammatory memory formed larger tumors, effectively lowering the threshold for transformation.
Same mutation, different outcome depending on the cell’s past experiences.
It’s well known that inflammation increases cancer risk, but how?
The answer: the epigenome "remembers" inflammation and primes stem cells for cancer.
Here is our paper: nature.com/articles/s41...
And a special shoutout to the lead author
@snaga13.bsky.social
A 🧵
In my lab, we are driven by the simple idea: epigenomes are drivers of disease.
We asked whether inflammation leaves lasting epigenetic changes that quietly predispose cells to become cancerous.
The epigenome: genome.gov/genetics-glo...
To test this, we turned to a mouse model of chronic colitis, where we could control when inflammation happens, when it resolves, and what comes next.
This gave us a clean way to ask: does past inflammation leave a lasting imprint on cells?
Chronic gut inflammation leaves behind “molecular scars” that may raise the risk for developing cancer, according to a new study showing that epigenetic memory of colitis, along with a cancer-promoting mutation, can accelerate tumor growth in mice. @jbuenrostro.bsky.social
Broad has launched the Biology of Adversity Project, led by
@jbuenrostro.bsky.social a 2023 @macfound.org fellow, to uncover how adverse life experiences can inflict molecular “scars” in the genome and body and increase risk of heart disease and other disorders. Learn more: broad.io/BAP
We’re excited to report work led by postdoc Jennifer Porat in the lab, finding that DNA accumulates on the surface of living cells and that the secreted extracellular protein DNASE1L3 can modulate its levels on B and T cells. With a new twist for ATAC-seq as well www.biorxiv.org/content/10.1...
I’m thrilled to share my postdoc work and the first paper from the McKinley Lab! 🎉
@karalmckinley.bsky.social
We built the first transgenic model of menstruation in mice.
We used it to uncover how the endometrium organizes and sheds during menstruation. 🧪
www.biorxiv.org/content/10.1...
🧵
Congratulations @karalmckinley.bsky.social & lab on their groundbreaking recent preprint establishing + characterizing a chemically inducible model of menstruation in mouse:
www.biorxiv.org/content/10.1...
My jaw dropped when I heard this presented earlier this year. Incredible.
Leading epigenetics researcher and longtime Broad member
@jbuenrostro.bsky.social has been named core institute member of the Broad. His lab will study how cells change in response to life experiences, and how those alterations affect health and disease.
One last thing - I am on the job market! My lab will extend this approach to decode resilient chromatin: adaptations in proteins/DNA that allow for survival in harsh environments. These hold the 🔑 to designing cells that thrive under stress, esp. as we push the limits of where we take them ❄️🚀🪐🌱9/9
Huge thanks to all co-authors and the inimitable @jbuenrostro.bsky.social for supporting this new direction - I got to think about evolution, engineering, chromatin biophysics, and modeling during the course of this project. For more, check out the preprint: www.biorxiv.org/content/10.1... 8/9
Excited to share my postdoc work, out on bioRxiv today! Histones package DNA into nucleosomes to form the building blocks of chromatin, but how modular and programmable is this system? 1/9
Had a super week filled with great science, curiosity and discussions at this year's Gordon Research Conference on Human genetics and genomics. Also fun when you get to give a talk the same day as your postdoc advisor @jbuenrostro.bsky.social
Excited to be attending this year's Human genetics and genomics Gordon Research Conference in Portland, ME, where I'll be presenting work from @gordianbio.bsky.social related to our in vivo mosaic screening platform applied to accelerate patient-relevant target discovery in complex diseases!
Honored to be an HHMI FHS! Grateful to brilliant colleagues who push me to think deeply, and to my students whose curiosity & energy make the lab a joy.
My grad advisor said in genetic screens, you don’t get what you want—you get what you deserve. Hope we are deserving
www.hhmi.org/programs/fre...
Epigenetics Update - Expansion in situ genome sequencing links nuclear abnormalities to aberrant chromatin regulation bit.ly/4jtXApb
Jason D. Buenrostro (MIT/Harvard) reporting in Science
#Epigenetics#Chromatin
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Gain deeper insights into gene regulation; epigenometech.com
Disease diagnostics using machine learning of B cell and T cell receptor sequences
www.science.org/doi/10.1126/...
TL;DR: BCRs ARE ALL YOU NEED!
(Well actually .... keep reading) 1/
We’d like to thank our collaborators in the Yilmaz and Breault labs, and PROSPECT @cancerresearchuk.org / NCI for their support. Find out about binding partners, drugging AP-1, the new tools we made and more here at our pre-print: tinyurl.com/ColitisNagar... (14/14)
New to bluesky, but I’m excited to share my work over the last few years with @jbuenrostro.bsky.social! Chronic inflammation creates an epigenetic memory in colonic stem cells, priming them for tumor growth: tinyurl.com/ColitisNagar.... Here’s a walkthrough of what we found (🧵)
To help people understand the importance of NIH, share what you’ve used their funding for (in easily understandable terms).
I’ll start: my NIH postdoc funding helped me develop and test AI tools that could identify skin cancer across diverse skin tones.
Super excited to share our new study from the @jbuenrostro.bsky.social Lab in @nature.com! We developed a computational method for tracking transcription factor and nucleosome binding using single-cell ATAC-seq and deep learning.
Paper: www.nature.com/articles/s41...
I’m celebrating tonight with my father in law, Jack Strominger, who is about to enjoy his 100th New Years!
He wants to know whether any other scientist has published in their 100th year. He’s proud to have a paper in the works. I told him you all would know! Please RT
Our ChromBPNet preprint out!
www.biorxiv.org/content/10.1...
Huge congrats to Anusri! This was quite a slog (for both of us) but we r very proud of this one! It is a long read but worth it IMHO. Methods r in the supp. materials. Bluetorial coming soon below 1/
Aiming to release our long awaited ChromBPNet preprint by early next week as well. I'm recovering from back to back infections for the past 6 weeks. But we're almost there. We have some solid variant prediction benchmarks in there against large supervised models and lots more. Stay tuned.
Thrilled to see this paper out!! 🧪
Spatial transcriptomics of brain aging and 'spatial aging clocks' identify cells that have pro-aging or pro-rejuvenating effects on their neighbors!
Huge CONGRATS to Eric Sun and all authors! Fantastic collaboration with @jameszou.bsky.social!
rdcu.be/d33uQ 🧵
🧪 E11 Bio is excited to share a major step towards brain mapping at 100x lower cost, making whole-brain connectomics at human & mouse scale feasible (🧠→🔬→💻). Critical for curing brain disorders, building human-like AI systems, and even simulating human brains.
Read more: e11.bio/news/roadmap