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Mutations in the splicing factor RBM20 cause aggressive Dilated Cardiomyopathy. Here the authors generated RBM20 R636S mutants and knockout in human iPSC-derived cardiomyocytes. Mutant RBM20 showed different target RNA binding, altered splicing and localization to cytoplasmic processing bodies.

Singh and colleagues show Tigit controls the generation of germinal center-derived plasma cell precursors that give rise to long-lived differentiated progeny in the bone marrow.

Grimes and colleagues integrate multiomic features to create a framework that allows the isolation of discrete cell states across hematopoiesis and exploit the underlying gene regulatory networks to identify lineage restriction within multilineage progenitors.

Basu et al. find that the transcription factor ThPOK is not restricted to T cells, as it also is expressed in myeloid cell progenitors and contributes to the lineage choice of monocyte-dendritic cells as opposed to neutrophils.

Single-cell genomics has expanded to measure diverse molecular modalities within the same cell. Here the authors provide a computational framework called scTriangulate to integrate cluster annotations from diverse independent sources, algorithms, and modalities to define statistically stable populations.

Mouse models of severe congenital neutropenia using patient-derived mutations in the GFI1 locus are used to determine the mechanisms by which the disease progresses.

Stem cells generate progenitors that transition through a series of dynamically unstable states with mixed-lineage gene expression, culminating in the specification of cell-fate.

Accurate cell-type identification is vital for single-cell analysis. Here, the authors develop a computational pipeline called “LungMAP CellRef” for efficient, automated cell-type annotation of normal and disease human and mouse lung single-cell datasets.

Human induced pluripotent stem cell derived cardiomyocytes are a powerful model for cardiogenesis and disease in vitro. Here the authors comprehensively map cardiac differentiation using multiple modalities, including single-cell RNA seq and CyTOF, in cells with a gain  or loss of function in key cardiac transcription factors.

Analysis of exomes and transcriptomes from 100 African American patients with acute myeloid leukemia identifies ancestry-related variation in mutation profiles and survival. Refined risk classification suggests clinical relevance of these ancestry-associated differences.

Starczynowski and colleagues show that overexpression of TRAF6 in HSCs induces ubiquitination of the RNA-binding protein hnRNPA1 and alternative splicing of Arhgap1, which accounts for the hematopoietic defects in myelodysplastic syndromes.

In this Resource article, the authors integrate genomic, bioinformatic and flow cytometric data from human bone marrow to provide an atlas of hematopoietic progenitor cell states in health and disease.

Nr2fs are conserved transcription factors that regulate atrial chamber and venous development. Here, the authors use adult zebrafish nr2f1a mutants to investigate compensatory remodeling of the inflow tract and hypotheses of cardiac evolution.

Xu and colleagues use single-cell transcriptomic analyses to uncover distinct expression dynamics of metabolic programs in germinal center B cells. Coupled analysis of transcriptional states and Igh variable sequences revealed that OXPHOS metabolism is enhanced in GC B cells undergoing positive selection. Their findings suggest BCR signaling tunes GC B cell metabolism to accelerate the cell cycle of positively selected GC B cells.

The cessation of nephrogenesis determines nephron endowments in mammals. Here the authors show that differential translation of Wnt antagonists versus agonists determines the tipping point from self-renewal to differentiation of nephron progenitors during nephrogenesis, using mutant mice with elevated nephron numbers.

Mammalian skeletal muscle is composed of multinucleated myofibers, containing hundreds of nuclei that coordinate cellular function. Here, the authors show that single-nucleus RNA-sequencing reveals rare and emergent myonuclear populations, and uncovers dynamic transcriptional heterogeneity in development and aging.

Smith et al demonstrate that mutated splicing factor U2AF1 promotes expression of a longer isoform of IRAK4, leading to enhanced NF-kB activation and leukaemic growth in acute myeloid leukaemia.

The alternative splicing regulator MBNL1 is overexpressed in MLL-rearranged leukaemia. Here, the authors show that MBNL1-mediated alternative splicing leads to a specific splicing profile in MLL-rearranged leukaemia and loss or inhibition of MBNL1 impairs leukaemia development in vitro and in vivo.

A combination of fluorescent antibodies is used to build visual maps of all myeloid cells in the bone marrow, providing new insight into how the bone marrow microenvironment regulates cell-fate decisions.

Fibroblast-to-myofibroblast differentiation is crucial for wound healing and regeneration. Davis et al. describe a new regulatory mechanism underlying myofibroblast differentiation via the RNA-binding protein MBNL1, which promotes the maturation of certain mRNA transcripts that are integral nodes in fibroblast differentiation.

Transcription elongation (TE) is a key point of inducible gene expression regulation. Here, the authors report widespread TE defects (TE^deff) in a high proportion of cancers that correlate with poor immunotherapy response, highlighting TE defects as potential routes for immune resistance.

Epigenetic and transcriptomic differences in human induced pluripotent stem cells generated from the same fibroblast population reveals that the reprogramming method affects the cells’ gene-expression levels but not their differentiation potential.

Linking transcription factors with disease loci implicates EBNA2, encoded by Epstein–Barr virus, in autoimmune diseases. Applying the method more widely identifies associations for hundreds of transcription factors, illuminating disease mechanisms.

Different types of stromal cells in the bone marrow associate to form niches that support differentiating blood cells and ensure lifelong production of all major blood lineages. A study now combines single-cell and spatial transcriptomics with imaging to infer the cellular composition and spatial architecture of specific niches.

The Impact of Genomic Variation on Function Consortium is combining single-cell mapping, genomic perturbations and predictive modelling to investigate relationships between human genomic variation, genome function and phenotypes and will provide an open resource to the community.

Lape et al. use electronic health records and a discovery-replication cohort study design to investigate links between common pathogens and non-communicable diseases. Evidence is found for over 200 associations, such as a role for human cytomegalovirus in ulcerative colitis.