John G. Doench

A pooled CRISPR screen reveals genes critical for erythroblast enucleation

This study uses a CRISPR screen to identify genes critical for erythroblast enucleation, finding CLIC3 and VAMP8 as key factors with distinct roles in the process.

Combinatorial CRISPR/Cas12a excises targeted loci in the mammalian genome at very low efficiency

This study evaluates combinatorial CRISPR/Cas12a for locus excision in mammalian cells and finds low efficiency despite targeting intronic regions.

Dynamic inositol pyrophosphate synthesis is a targetable therapeutic opportunity in ovarian cancer.

This study evaluates strategies to inhibit XPR1 in ovarian cancer, showing that IP6K inhibitors effectively mimic XPR1 inhibition by blocking phosphate efflux and reducing tumor burden in xenograft models.

A transcriptional biosensor reveals mechanisms of α-ketoglutarate signaling to chromatin

The paper develops a biosensor to monitor α-ketoglutarate in human cells and identifies a mitochondrial-to-nuclear pathway regulating chromatin methylation.

Direct comparison of CRISPR knockout and interference with Perturb-seq

This study compares CRISPR knockout and interference using Perturb-seq, finding consistent transcriptional signatures and tradeoffs in off-target activity and cellular response artifacts.

Discovery of Tcf7 regulators with clonally-resolved CRISPR screens identifies Trim28 as a mediator of CD8 T cell differentiation in tumors

The paper identifies Trim28 as a regulator of CD8 T cell differentiation in tumors using clonally-resolved CRISPR screens and shows its role in maintaining TCF7+ stem-like cells while impairing effector differentiation.

Genome-wide CRISPR interference screen identifies Clip2 as a novel regulator of osteocyte maturation and morphology

The paper uses a CRISPRi screen to identify Clip2 as a regulator of osteocyte maturation and morphology by analyzing CD61 expression and dendrite formation.

CD164 is an endolysosomal host factor for entry of Clade A New World Arenaviruses

The paper identifies CD164 as an endolysosomal receptor for clade A New World arenaviruses, expanding the receptor switching paradigm observed in Old World arenaviruses.

KDM6 Enzymes are the Mechanistic Targets of Mutant IDH that Dictate Replication Stress Sensitivity

This study identifies KDM6 enzymes as targets of R2HG from mutant IDH, linking them to replication stress sensitivity in gliomas and introduces a DHODH inhibitor, GLIO-1, with potential clinical applications.

Balancing off-target and on-target considerations for optimized Cas9 CRISPR knockout library design

The paper presents a guide selection strategy to optimize Cas9 CRISPR knockout library design by balancing on-target and off-target activity, resulting in an updated validated library for the human genome.

Optimized parameters for Cas9 CRISPR interference library design

This study designs an optimized Cas9 CRISPRi library by improving on-target scoring and analyzing off-target effects using updated datasets and methods.

CLCC1 promotes membrane fusion during herpesvirus nuclear egress.

The paper identifies CLCC1 as a host factor essential for herpesvirus nuclear egress fusion, showing its role in membrane fusion and nuclear envelope morphogenesis.

Host cyclophilin-mediated maturation of an obligate intracellular bacterial surface virulence factor

This study identifies cyclophilin A as a host factor critical for the maturation and function of a virulence factor in obligate intracellular bacteria, with implications for therapeutic targeting.

Activity-based selection for enhanced base editor mutational scanning

This paper introduces an activity-based selection method to improve base editing efficiency and precision in identifying functional mutations.

In vivo CRISPR screens identify key modifiers of CAR T cell function in myeloma

The paper uses in vivo CRISPR screens to identify genes affecting CAR T cell persistence and function in multiple myeloma, finding CDKN1B as a key regulator of late-stage CAR T cell fitness.

Morphological map of under- and over-expression of genes in human cells

The paper presents a comprehensive genetic perturbation dataset using Cell Painting to analyze gene expression effects in human cells, revealing novel gene clusters and functional relationships.

Cyclin A/B RxL Macrocyclic Inhibitors to Treat Cancers with High E2F Activity

This paper develops cyclin A/B macrocyclic inhibitors that induce apoptosis in cancers with high E2F activity by blocking RxL-mediated interactions, showing efficacy in SCLC models.

Discovery of chromatin-based determinants of azacytidine and decitabine anti-cancer activity

This study identifies DNA hypomethylation, not DNA damage, as the primary mechanism of azacytidine and decitabine anti-cancer activity, linking it to chromatin regulators like USP48.

Sialylated CD43 is a glyco-immune checkpoint for macrophage phagocytosis

The paper identifies CD43 as a glyco-immune checkpoint that inhibits human macrophage phagocytosis, showing that O-linked glycosylation and sialylation pathways regulate this process in AML.

CREB5 promotes immunotherapy resistance via tumor-intrinsic collagenmatrix deposition

The paper identifies CREB5 as a driver of immunotherapy resistance in melanoma by promoting collagen matrix deposition, which activates LAIR1 signaling on immune cells.

HKU5 bat merbecoviruses use divergent mechanisms to engage bat and mink ACE2 as entry receptors

This study identifies bat and mink ACE2 as receptors for HKU5 merbecovirus, revealing distinct receptor interactions and highlighting mustelids as potential intermediate hosts.

Multi-locus CRISPRi targeting with a single truncated guide RNA

This paper develops a CRISPRi approach using truncated guides to screen multiple transcription factor binding sites, showing they can disrupt enhancer activity and repress transcription factor binding.

Cancer target discovery enabled by transcriptome-based virtual CRISPR screening

This study uses machine learning to infer gene dependencies from tumor transcriptomes, identifying cancer vulnerabilities in rare cancers without experimental screening.

Comprehensive structure-function analysis reveals gain- and loss-of-function mechanisms impacting oncogenic KRAS activity

This study uses deep mutational scanning to analyze KRAS variants, identifying gain- and loss-of-function mechanisms and their impact on oncogenic activity.

Three million images and morphological profiles of cells treated with matched chemical and genetic perturbations

The paper introduces a dataset of cell morphology images treated with matched chemical and genetic perturbations and evaluates methods for identifying perturbation similarities.

Modular vector assembly enables rapid assessment of emerging CRISPR technologies

The paper introduces a modular CRISPR vector assembly system called Fragmid, enabling rapid creation and testing of CRISPR technologies through combinatorial design and pooled screening.

Proteome-wide base editor screens to assess phosphorylation site functionality in high-throughput

The paper uses base editor screens to assess phosphorylation site functionality in T cell activation, identifying novel sites that modulate transcriptional activity and signaling pathways.

Optimization of Cas12a for multiplexed genome-scale transcriptional activation

The paper optimizes Cas12a for multiplexed CRISPRa screens in human cells, enabling simultaneous activation of up to four genes and identifying criteria for selecting effective guides.

JUMP Cell Painting chemical dataset: Morphological map of 115,796 compounds in human cells

Cell Painting images and profiles for 115,796 compounds in U2OS cells from 12 laboratories; 15.2% of analyzed compounds are phenotypically active, and cross-laboratory replicates cut reference-compound activity by 34%.

Systematically characterizing the roles of E3-ligase family members in inflammatory responses with massively parallel Perturb-seq

The paper uses Perturb-seq to systematically study 1,130 E3 ligases and their roles in inflammatory responses in dendritic cells, revealing co-functional modules and genetic interactions.