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Five leading researchers provide their perspectives on our current understanding of pioneer factors and their important gene regulatory roles in cell differentiation, cell fate determination and reprogramming.

Here, the authors perform large trans-ancestry fine-mapping analyses identifying large numbers of association signals and putative target genes for colorectal cancer risk, advancing our understanding of the genetic and biological basis of this cancer.

Authors perform an analysis of the patient data and risk factors to evaluate unfavorable outcomes and adverse events in adults with pulmonary tuberculosis treated with a 4-month rifapentine based regimen. Low rifapentine exposure was the most clinically significant risk factor for treatment failure and tuberculosis relapse.

DNA methylation is an epigenetic mark that plays a critical role in many biological processes. Here, we describe the development of SAM-DNMT3A a tool for induction of genome wide DNA methylation. Using SAM-DNMT3A we show that DNA methylation is a unique vulnerability in ER+ breast cancer.

Phylogenomic analysis of 7,923 angiosperm species using a standardized set of 353 nuclear genes produced an angiosperm tree of life dated with 200 fossil calibrations, providing key insights into evolutionary relationships and diversification.

Ikaros, Helios and Aiolos are transcription factors involved in lymphocyte development. Here the authors dissect the regulatory role of these Ikaros family members to understand their contribution to NK cell development and functions.

The proximal femur of the early hominin Orrorin tugenensis presents a mosaic of earlier Miocene ape and later hominin features. Here, Almécija et al. show that hominin and modern great ape femura diverged from an ancestral morphology and that Orrorinis intermediate between Miocene apes and australopiths.

A multi-ancestry genome-wide association study meta-analysis, combined with transcriptome- and methylome-wide association analyses, identifies risk loci associated with colorectal cancer. Credible effector genes and their target tissues are also highlighted, showing that over a third probably act outside the colonic mucosa.

Genome-wide association analyses based on whole-genome sequencing and imputation identify 40 new risk variants for colorectal cancer, including a strongly protective low-frequency variant at CHD1 and loci implicating signaling and immune function in disease etiology.

By investigating key transcription factors in Drosophila, the authors show that pioneering activity is not an intrinsic, binary property. Instead, it is heavily influenced by the level of chromatin occupancy of the transcription factors, which is controlled by multiple protein domains and protein-extrinsic features.

Whole-genome sequencing analysis of individuals with primary immunodeficiency identifies new candidate disease-associated genes and shows how the interplay between genetic variants can explain the variable penetrance and complexity of the disease.

Using quantitative imaging and monitoring transcription in living embryos, Bellec et al., provide evidence that the pioneer factor GAF acts as a stable mitotic bookmarker during early Drosophila development.

In this immunological ancillary study of the PREVAC trial, the authors show that approved Ebola virus vaccines induce memory T-cell responses that persist during the five year follow-up after initial vaccination.

The genome of the biofuel crop switchgrass (Panicum virgatum) reveals climate–gene–biomass associations that underlie adaptation in nature and will facilitate improvements of the yield of this crop for bioenergy production.

The pioneer transcription factor Zelda is essential for the reprogramming of germ cells to totipotent cells of the early Drosophila embryo. Here the authors examine the function of Zelda later in development in the larval brain to show that Zelda promotes the undifferentiated stem-cell fate. They further identify factors that limit the reprogramming capacity of this pioneer factor.

The high spatial resolution of secondary ion mass spectrometry and the high resolving power of the Orbitrap mass spectrometer are combined in a single imaging platform, the 3D OrbiSIMS. The instrument's capabilities for resolving lipids and neurotransmitters in the brain with subcellular spatial resolution, and a drug in a single cell in three dimensions is demonstrated.

Chromodomain Helicase DNA-binding (CHD) proteins have been implicated in neurodevelopmental processes. Here, the authors identify missense variants in CHD3 that disturb its chromatin remodeling activities and cause a neurodevelopmental disorder with macrocephaly and speech and language impairment.

Activation of the adenosine receptor A2AR is associated with suppression of T cell function in the tumor microenvironment. To overcome immunosuppression, here the authors show that CRISPR/Cas9 mediated deletion of A2AR enhances CAR T cell effector functions without altering memory or persistence properties, improving CAR-T mediated tumor control in pre-clinical models.

Whole-exome analysis of individuals with developmental disorders shows that de novo mutations can equally cause loss or altered protein function, but that most mutations causing altered protein function have not yet been described.

Zelda is a pioneer factor that regulates transcription in Drosophila embryos. Here, the authors use quantitative live imaging and mathematical modeling to measure the effect of Zelda on transcriptional dynamics and memory, observing temporal control of gene expression by Zelda through transient interactions in hubs.

Developmental disorders (DDs) are more prevalent in males, thought to be due to X-linked genetic variation. Here, the authors investigate the burden of X-linked coding variants in 11,044 DD patients, showing that this contributes to ~6% of both male and female cases and therefore does not solely explain male bias in DDs.

Identification and characterization, using a comprehensive embryonic phenotyping pipeline, of 410 lethal alleles during the generation of the first 1,751 of 5,000 unique gene knockouts produced by the International Mouse Phenotyping Consortium.

A study describes the release of clinical-grade whole-genome sequence data for 245,388 diverse participants by the All of Us Research Program and characterizes the properties of the dataset.

By integrating healthcare and exome-sequencing data from parent–offspring trios of patients with developmental disorders, 28 genes that had not previously been associated with developmental disorders were identified.

Bacteria use a range of regulatory strategies to control replication initiation, many of which are tightly connected to the activities of the bacterial initiator DnaA. Here, Melissa Mott and James Berger review our current understanding of the mechanisms and regulation of bacterial DNA replication initiation, with a particular emphasis on DnaA.

The LITMUS consortium provides a resource of rodent MASLD models benchmarked against metabolic, histologic and transcriptomic features that are relevant for human MASLD. The work is useful for selecting relevant rodent models for studying this common disease.

Global Natural Product Social Molecular Networking (GNPS) is an online tandem mass spectrometry (MS²) data curation and analysis infrastructure. This protocol describes how to use GNPS to explore uploaded metabolomics data.

The maternal-to-zygotic transition (MZT) is the process by which the transcriptionally silent embryonic genome is gradually activated. The mechanisms underlying the MZT are not fully understood, but recent work indicates that transcriptional activators have an important role.

Assessing the genetic variation of bacteria has become ever more complex as more sequencing data has become available. Here, Maiden and colleagues propose a gene-by-gene approach of analysing whole-genome data; this approach is based on their experience with multilocus sequence typing (MLST) and reflects the functional and evolutionary relationships among bacteria.