Combinatorial effector targeting (COMET) for transcriptional modulation and locus-specific biochemistry.

Understanding how human gene expression is coordinately regulated by functional units of proteins across the genome remains a major biological goal. Here, we present COMET, a high-throughput screening platform for combinatorial effector targeting for the identification of transcriptional modulators. We generate libraries of combinatorial dCas9-based fusion proteins, containing two to six effector domains, allowing us to systematically investigate more than 110,000 combinations of effector proteins at endogenous human loci for their influence on transcription.

Deciphering cell states and genealogies of human haematopoiesis.

The human blood system is maintained through the differentiation and massive amplification of a limited number of long-lived haematopoietic stem cells (HSCs). Perturbations to this process underlie diverse diseases, but the clonal contributions to human haematopoiesis and how this changes with age remain incompletely understood. Although recent insights have emerged from barcoding studies in model systems, simultaneous detection of cell states and phylogenies from natural barcodes in humans remains challenging.

First experience with real-time magnetic resonance imaging-based investigation of respiratory influence on cardiac function in pediatric congenital heart disease patients with chronic right ventricular volume overload.

Background: Congenital heart disease (CHD) is often associated with chronic right ventricular (RV) volume overload. Real-time magnetic resonance imaging (MRI) enables the analysis of cardiac function during free breathing.

Objective: To evaluate the influence of respiration in pediatric patients with CHD and chronic RV volume overload.

Mapping information-rich genotype-phenotype landscapes with genome-scale Perturb-seq.

A central goal of genetics is to define the relationships between genotypes and phenotypes. High-content phenotypic screens such as Perturb-seq (CRISPR-based screens with single-cell RNA-sequencing readouts) enable massively parallel functional genomic mapping but, to date, have been used at limited scales. Here, we perform genome-scale Perturb-seq targeting all expressed genes with CRISPR interference (CRISPRi) across >2.