Jason Buenrostro

Jason Buenrostro

@jbuenrostro.bsky.social

Epigenetics & Genomics Harvard University & Broad Institute https://www.macfound.org/fellows/class-of-2023/jason-d-buenrostro buenrostrolab.com

2.1K followers166 following36 posts

Jason Buenrostro reposted

1/13 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...

biorxiv.orgSingle-Nucleus Multi-Omic Atlas Maps Regulatory Architecture and Non-Coding Variant Effects across Adult Human TissuesDiverse human cell types establish specialized functions through lineage- and context-specific regulatory programs. Interpreting non-coding genetic risk requires integrated multi-omic reference maps t...

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!

Broad Institute@broadinstitute.org

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.

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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. 🧬

nature.comMultiscale footprints reveal the organization of cis-regulatory elements - NatureWe developed PRINT, a computational method that identifies footprints of DNA–protein interactions from bulk and single-cell chromatin accessibility data across multiple scales of protein size.
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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.

Jason Buenrostro reposted

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.

Jason Buenrostro reposted

Jason Buenrostro@jbuenrostro.bsky.social

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.

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?

Jason Buenrostro reposted

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.ioHow inflammation may prime the gut for cancerA study in mice suggests that even intestinal cells that appear healthy may hold epigenetic “memories” of earlier bouts of inflammation that can promote colon cancer later in life.

Jason Buenrostro reposted

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...

biorxiv.orgDNASE1L3 surveils mitochondrial DNA on the surface of distinct mammalian cellsThe extracellular space is a critical environment for discriminating self versus non-self nucleic acids and initiating the appropriate immune responses through signaling cascades to relay information ...

Jason Buenrostro reposted

Jason Buenrostro reposted

Jason Buenrostro reposted

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.

broad.ioJason Buenrostro named core institute member at BroadAn expert in epigenetics and longtime member of the Broad community, Buenrostro will focus on how life experiences can alter the epigenome and increase risk of disease.

Jason Buenrostro reposted

Replying to @epijenatics.bsky.social

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

Jason Buenrostro reposted

Replying to @epijenatics.bsky.social

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

biorxiv.orgEngineered histones reshape chromatin in human cellsHistone proteins and their variants have been found to play crucial and specialized roles in chromatin organization and the regulation of downstream gene expression; however, the relationship between ...

Jason Buenrostro reposted

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

Jason Buenrostro reposted

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

Vinay Kartha@vkartha.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!

Jason Buenrostro reposted

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...

hhmi.orgThe 2025 Freeman Hrabowski Scholars | HHMIFreeman Hrabowski Scholars are outstanding early career faculty who have the potential to become leaders in their research fields.

Jason Buenrostro reposted

Jason Buenrostro reposted

Jason Buenrostro reposted

Jason Buenrostro reposted

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.

Jason Buenrostro reposted

Jason Buenrostro reposted

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

Jason Buenrostro reposted

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/

biorxiv.orgChromBPNet: bias factorized, base-resolution deep learning models of chromatin accessibility reveal cis-regulatory sequence syntax, transcription factor footprints and regulatory variantsDespite extensive mapping of cis-regulatory elements (cREs) across cellular contexts with chromatin accessibility assays, the sequence syntax and genetic variants that regulate transcription factor (T...
Anshul Kundaje@anshulkundaje.bsky.social

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.

Jason Buenrostro reposted

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 🧵

rdcu.beSpatial transcriptomic clocks reveal cell proximity effects in brain ageingNature - A spatially resolved single-cell transcriptomics map of the mouse brain at different ages reveals signatures of ageing, rejuvenation and disease, including ageing effects associated with T...

Jason Buenrostro reposted

🧪 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