Thrilled to share our latest work! We identified and engineered a miniature, nuclease-dead xCas12m that enables effective epigenome editing. Combined with CRISPRoff, it achieved durable silencing and inhibition of HBV via single-AAV delivery. Huge congrats to the team!👏

Inspired by Gibson cloning, we describe prime assembly, now published, for in cellulo targeted integration of gene-sized DNA fragments using prime editing. nature.com/articles/s41586-0…

ONLINE NOW in @CellCellPress: McBrayer Lab's #relentlessdiscovery finds 100-fold accumulation of metabolite GAA overstimulates nearby neurons to fuel aggressive brain tumor growth. Read more ⬇️ cri.utsw.edu/scientists-disc…

ONLINE NOW in @ScienceTM from CRI's McBrayer Lab: Full 🧵 in comments ⬇️ #relentlessdiscovery science.org/doi/10.1126/scit…

Really enjoyed reading this excellent and thought-provoking new review on long-range enhancer-mediated gene regulation: nature.com/articles/s41588-0…

(1/n) Excited to share close collab w @bloodgenes led by @VarshiniRam23 & @guo_chunjie et al How to induce expression of key genes while silencing much of the genome during Erythropoiesis? A: Matchmaker CREs load cohesin near key genes to promote looping biorxiv.org/content/10.64898…

TODAY in @dallasnews : Read more about McBrayer Lab's #relentlessdiscovery in @ScienceMagazine, with a cameo from CRI Genetic & Metabolic Disease Program Director Ralph DeBerardinis.

Glad to share our latest publication in Science! This work reports: 🧬 the first single-cell 3D genome atlas of human tonsil and B cell immunity, 🧬 the first image-based 3D genomics dataset of any human tissue, 🧬 a new function for cohesin loop extrusion, and 🧬 a novel chromatin "curl" structure. Antibody-mediated immunity relies on the generation of point mutations in rearranged immunoglobulin (Ig) loci of activated germinal center (GC) B cells. This process - called somatic hypermutation (SHM) - allows for antibody affinity maturation but also acts at certain non-Ig sites in the genome, thereby contributing to mutations and chromosomal translocations that drive B cell oncogenesis. My collaborator Prof. David Schatz's previous work indicates that SHM susceptibility is controlled by the cooperative action of cis-acting SHM target elements and the architectural properties of topologically associating domains (TADs), but how the genome is spatially organized across multiple length scales as GC B cells develop and activate SHM and how 3D genome architecture influences the targeting of SHM remains unknown. To test the functional requirement of 3D genome organization for SHM, in this work we developed a 3D genome and spatial transcriptome toolbox optimized for clinical tonsil tissue, and used it to define single cell 3D genome architectures and nuclear organization in GC B cells undergoing SHM in normal human tonsil samples and in malignant GC-derived human B cell lymphoma cell cultures. Our new work generated the following key insights: 🧬 At the large scale, the nuclear positioning of TADs is linked to SHM susceptibility, with the nuclear periphery being more permissive to SHM and the nuclear interior being more protected from SHM. 🧬 At the fine scale, increased intra-TAD looping contacts in gene regions are associated with SHM susceptibility. 🧬 Most importantly, through rapid, targeted degradation of cohesin component RAD21, our new results provide the first direct evidence that the cohesin mediated loop extrusion is essential for SHM. We further showed that the effects of loop extrusion on SHM cannot be solely attributed to transcription activity changes. This represents a brand new function of the famous loop extrusion process. 🧬 In addition, we serendipitously discovered a novel chromatin “curl” structure – a chromatin loop with two long (~25 kb) stem regions aligned in parallel with each other (distinct from e.g., CTCF anchored chromatin loops where two stems are aligned in an anti-parallel fashion). To our best knowledge, this is the first report of such a structure outside of the contexts of DNA recombination/transposition. I'd like to thank all my co-authors, especially co-corresponding author legendary immunobiologist Prof. David Schatz, and co-first authors Yubao, Jianshu, and Yuan. It has truly been a wonderful experience working with you. Link to paper: science.org/doi/10.1126/scie…

The Ly Lab @CRI_UTSW is recruiting two #postdocs to study intercellular DNA transfer. Join us to tackle fundamental questions at the intersection of genome instability, cell-cell communication, and cancer evolution. Please share! 🙏 Full posting: cri.utsw.edu/careers/

Masahiro and I were fortunate to contribute some RCMC analyses to this beautiful paper from Koska and Wysocka that comprehensively dissects the determinants of promoter competition: nature.com/articles/s41588-0…

Thyroid cancer-associated EZH1 Q571R mutation drives chromatin compaction and H3K27me3 invasion into active chromatin dlvr.it/TTdlRC

How to link a non-coding disease GWAS variant to its target genes in the right cell type? ENCODE-rE2G, now out in @Nature addresses this through optimal integration of chromatin activity and 3D contact data in 1,458 biosamples. A huge collaborative effort spanning 6+ years led by @argschwind @jengreitz nature.com/articles/s41586-0…

ONLINE NOW in @ScienceMagazine: Latest #relentlessdiscovery from CRI's McBrayer Lab uses their newly developed biosensor to track missing metabolite (αKG) in rare childhood brain disorder, GPT2 deficiency. Read more ⬇️ cri.utsw.edu/new-biosensor-t…

Nature research paper: Replication-stress-induced chromatin loops protect fork stability go.nature.com/4pjMkjT

Holiday mood-filled lab dinner at Zhang's Bistro with Peking Duck, spicy grilled fish, and my fav mapo tofu! @SihanSean @YoonKimUTSW @QK15622518 @LucasaEast @yipengxie_utsw

Very excited to share our new Nature study! We discovered that replication stress stabilizes CTCF-dependent chromatin loops enclosing stressed nascent DNA, where G9a-mediated heterochromatin protects it from nucleolytic degradation. nature.com/articles/s41586-0…

New online! Genome-wide absolute quantification of chromatin looping dlvr.it/TTHWPV

Sharing a new paper from the lab: How do ecDNAs segregate during cancer cell division? ecDNA lacks a centromere and needs to attach to mitotic chromosomes to be distributed to daughter cells. The question is: HOW? nature.com/articles/s41556-0… -1/x

Very excited to see our paper officially published online in Nature Cell Biology today! This project has been years in the making, with many challenges, revisions, and lessons along the way. Deeply grateful to everyone who contributed to this work. nature.com/articles/s41556-0…

ONLINE NOW in @Nature Cell Biology: ecDNA anchors to H3K27ac-marked active regions on chromosomes to survive normal mitotic cell division and persist into the next generation of daughter cells. Read more about the latest #relentlessdiscovery from CRI's Wu Lab ⬇️ cri.utsw.edu/mechanisms-for-… @yipengxie_utsw, @YoonKimUTSW & @SihanSean