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Experimental and Computational Advancements in Single-Cell Biology

• An early demonstration, in 18 cells, that revealed the potential for investigation and discovery at single-cell resolution
• The first demonstration of a massively parallel single-cell sequencing method called Drop-Seq, in keeping with the KCO’s realization that biological discoveries would require profiling massive numbers of single cells
• Invented innovative new methods to study, sequence and profile single nuclei (sNuc-seq, Div-Seq, and DroNc-seq, the first massively parallel single-nucleus RNA-seq)
• Developed Perturb-Seq, the first method for pooled CRISPR screens with scRNA-seq readout
• Developed computational tools to accompany new technologies, such as algorithms to discover cell types, their positions in tissue, their continuous states, temporal transitions, and functional interactions, and the molecular regulatory networks that govern them
• Applied new experimental and computational tools to patient samples, including pioneering the first single-cell analyses of cancer

Flagship projects

• Th17 cells – defined the regulatory circuits controlling the balance between healthy and pathogenic Th17 cells
• Retina – developed the single-cell RNA sequencing method Drop-Seq and used it to identify all the types of neurons in the retina, including previously unknown cell types
• Tumor ecosystems – pioneered the single-cell analysis of tumors and their environment, including immune cells
• Gut – developed a cell atlas of the small intestine, identifying new types of sensory cells

Collaborative projects

• Identified the role of core circadian clock genes in regulating leukemia stem cells (with Ben Ebert lab)
• Developed sNuc-Seq and Div-Seq to perform single-cell profiling in the adult brain and some tumors (with Feng Zhang lab)
• Invented method for single-nucleosome analysis of combinatorial histone modifications in cancer (Bradley Bernstein lab)

The Immunological Genome Project (ImmGen)

ImmGen (), led by Program PI Christophe Benoist, is a collaborative group of 20 immunology and computational biology labs dedicated to dissecting gene expression and its regulation in the mouse immune system. Since its inception in 2007, the consortium has been anchored at the ӳ����ý through longstanding collaboration with Aviv Regev, the ӳ����ý Genomics Platform, and the Klarman Cell Observatory (KCO).

Functioning as a collective enterprise marked by open discussion of strategies, unpublished results, and perspectives, ImmGen combines expertise across adaptive and innate arms of the immune system together with computational biologists equally invested in the outcomes. This integration has been highly enriching and broadened the diversity of results.

Each member lab contributes distinct expertise, typically focusing on a specific immune cell lineage or development of a particular technology. The roster has evolved, but many founding labs remain, and several scientists who first participated as postdocs now lead their own research groups. Priorities, new projects, and membership decisions are made collectively, through online discussions and at the well-attended annual ImmGen workshop.

Programs in the ImmGen consortium are organized along three main axes:

1. Building a highly granular compendium of gene expression data. This was initially achieved with purified cell populations including finely parsed lymphocyte or myeloid cell subsets, leading to seminal demonstrations of diversity in macrophages of different origins. More recently, single-cell RNA sequencing and spatial profiling have enabled exploration of immune lineage diversity.
2. Analyses of gene regulation, regulatory RNAs, chromatin accessibility, and the 3D-nucleome have mapped the underlying regulatory genome across all immune cell types. These efforts have long been supported by a strong community of computational biologists, whose approaches have progressed from classic network inference to deep learning methods.
3. To serve its mission as a public resource, the group has developed web and smartphone visualization tools to disseminate data and provide interactive access. Community impact is a key metric, and ImmGen’s website has drawn ~300 visits per weekday for the last decade from across the global immunology community. ImmGen’s initial “Project Description” publication has been cited more that 2,100 times, underscoring the consortium’s broad influence.

Leveraged projects

• Analyzed additional tumor ecosystems, including glioma, synovial sarcoma, and head and neck squamous cell carcinoma (with Mario Suva, Bradley Berstein, and Nicolo Riggi labs)
• Characterized the lung epithelium in health and allergy (with Vijay Kuchroo lab)