Yale Department of Genetics
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@YaleGenetics
Official Twitter home of the Yale University Department of Genetics. Sharing the latest advances in genetics, news and upcoming events.
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/sc…
AFAY is honored to invite National Academy of Sciences members and emeritus HHMI investigators, Professor Lily Jan and Professor Yuh-Nung Jan from UCSF to give three talks at Yale on their research and on “Scientific Excellence, Mentorship, and Equity”. (1/3)
