We're very excited to launch of the Duke Center for Advanced Genomic Technologies @DukeCAGT, a joint venture of @DukeEngineering @DukeMedSchool and @DukeTrinity. We are supporting collaborative research efforts to tackle grand challenges in genome sciences and engineering.

Led by Sean McCutcheon, Dahlia Rohm, and Nahid Iglesias - we are thankful to the editors and reviewers for their contributions to enhancing this review.

We propose remaining challenges and opportunities for epigenome editing, and provide a future outlook. We are incredibly enthusiastic about the pace of new technology development in this area, the fundamental discoveries it is enabling, and what it can do for patients!

We explain the technology and its context among other genome editing tools, provide a catalog of common epigenome editors, survey recent technical advances, and summarize use cases in functional genomics, cell engineering, and gene/cell therapy.

Epigenome editing is transforming biological sciences and medicine. We're grateful for the opportunity to publish this review of the field in @NatureBiotech. Check it out here:

Epigenetic control is incredibly powerful for bolstering cell therapy. We’re very excited to continue to build on the foundation established with this publication.

Using a new CRISPR-based methodology, a team of researchers led by @cgersbach @DukeU has identified a “master regulator” gene capable of dramatically improving T-cell therapy performance >>>

Epigenetic CRISPR screening in human T cells reveals that BATF3 overexpression enhances T cell function, reduces exhaustion, and boosts CAR T cell potency in both in vitro and in vivo tumor models. #NBThighlight

We are incredibly thankful to our collaborators and co-authors, and our funding sources for supporting this new research direction! @somaticediting @ENCODE_NIH @IGVFConsortium @genome_gov @NSF @AllenInstitute @DukeU @DukeCAGT

This is our first report of a broader active area within our research group on T cell engineering. We are excited to repurpose the tools and protocols developed here for improve ACT and CAR-T for diverse applications. We’re looking forward to sharing more on these efforts soon!

Finally, Sean completed a CRISPR knockout screen to map co-factors or inhibitors of BATF3 to further enhance ACT engineering. Again, we found known and new factors that work independently or together with BATF3. More to come on these targets!

Genes that were previously associated with clinical responders or non-responders to ACT were upregulated or downregulated, respectively, by BATF3. This suggests that we are driving the epigenetic programs that lead to positive outcomes in difficult clinical oncology settings.

But how do we know if these epigenetic changes will matter when treating patients? We compared gene expression changes in BATF3-engineered cells to differences in gene programs observed between ACT products that were successful or not in generating responses in clinical trials.

In fact, the BATF3-engineered T cells showed enhanced killing of cancer cells in vitro and control of human tumor growth in a mouse model. Further characterization indicated epigenetically improved T cell function, not simply increased T cell numbers.

BATF3 was previously implicated in T cell function, but it was unknown whether BATF3 would improve ACT. We saw that BATF3 downregulated genes associated with T cell exhaustion and dysfunction, and upregulated genes involved in metabolism that could enhance anti-tumor activity.

We found many known and new modulators, and focused our attention on BATF3.

However working with primary human T cells required significant development of new CRISPR epigenetic screening technology, which Sean then used to profile master regulators of T cell states.

We saw this as a tremendous opportunity for epigenome editing technologies, which we have been developing for many years to discover and reprogram master regulators of cell differentiation and lineage specification.

Adoptive T cell therapy (ACT), including CAR-T, is revolutionizing cancer treatment. But while ACT has been very successful for some cancers, it often fails. Success of ACT has been linked to the T cells' epigenetic state that controls which gene programs are on or off.

Very happy to share our latest work today in @NatureGenet - "Transcriptional and epigenetic regulators of human CD8+ T cell function identified through orthogonal CRISPR screens" - led by @DukeUBME PhD student Sean McCutcheon. 1/n https://t.co/fv6O9oqnHi https://t.co/j17SgDHPDa

Looking forward to a great meeting!