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The authors identify genetic variation associated with properties of the internal biological structures of blood cells in hundreds of genes and show how such discoveries can be used to improve understanding of cellular mechanisms causing disease.

The Vertebrate Genome Project has used an optimized pipeline to generate high-quality genome assemblies for sixteen species (representing all major vertebrate classes), which have led to new biological insights.

The molecular processes that lead to neuroendocrine prostate cancer after treating prostate adenocarcinoma (PRAD) are not well understood. Here the authors show that regulation by FOXA1 and changes in the epigenomic profile drive the transition from PRAD to a neuroendocrine phenotype.

Sieweke and colleagues show that alveolar macrophages maintain a core gene expression program even after several months in culture and reacquire full transcriptional and epigenetic identity after transplantation into the lung.

A combination of genome-wide functional screening, imaging and chromatin profiling identifies a new class of highly prevalent genomic elements that help retain extrachromosomal DNA copies in dividing cells and persist across generations.

Multiple myeloma (MM) is an incurable blood malignancy. Here, the authors report 35 MM risk loci and two causal mechanisms for genetic MM risk: longer telomeres and elevated plasma B-cell maturation antigen (BCMA) and interleukin−5 receptor alpha (IL5RA) levels.

This multi-omic longitudinal analysis of the healthy human peripheral immune system constructs the Human Immune Health Atlas and assembles data on immune cell composition and state changes with age, including responses to cytomegalovirus infection and influenza vaccination.

Whole-genome sequencing and phenotype data sharing are introduced in a national health system to streamline diagnosis and to discover coding and non-coding variants that cause rare diseases.

Here, the authors functionally characterize a complex genetic variant relevant in prostate cancer that regulates IRX4 expression through epigenetic activation. This work highlights the significance of non-single nucleotide polymorphism causal variants in explaining disease risk.

Yolk sac erythro-myeloid progenitors (EMPs) are critical for embryo viability and a major source of adult tissue-resident macrophages. Here, the authors show an essential stage-specific role for Ezh2 in modulating Wnt signaling during EMP generation.

Richter’s Transformation is a treatment-resistant and fatal progression from Chronic Lymphocytic Leukemia (CLL) to an aggressive lymphoma. Here, the authors show that PRMT5 is upregulated months prior to and after transformation, PRMT5 overexpression in a CLL mouse model leads to increased risk of transformation, and that targeted PRMT5 inhibition prolongs survival and delays disease development.

Hoetker et al. show that H3K36 methylation exerts a dual role in cell identity maintenance: it integrates TGFβ signals at mesenchymal targets to keep them active and prevents the activation of alternative lineage programmes via enhancer methylation.

Smith et al. present a resource detailing drivers of transcriptional heterogeneity of synovial fibroblasts cell states in the inflamed joints of human patients with rheumatoid arthritis.

As studies continue sequencing with deeper coverage, computational processing of these profiles has become increasingly resource consuming. Here the authors designed an efficient computational method called Chromap to align and preprocess high throughput sequencing data from chromatin profiling techniques, including ChIP-seq, Hi-C, or scATAC-seq, with a major decrease in runtime.

The presence of bivalent epigenetic active and repressive histone marks control lineage-specific differentiation in embryonic stem cells. Here, the authors reveal that bivalent marks repress the differentiation gene IHH in colorectal cancer-initiating cells, and can be targeted by EZH2 inhibition

Chromosome rearrangements can be a cause of altered oncogene expression in cancer, such as a 3q26 translocation in some acute myeloid leukemias (AML) that leads to overexpression of EVI1. Here the authors engineer this rearrangement in a cell line and show that EVI1 overexpression is a result of ‘enhancer hijacking’ of the MYC superenhancer, which is facilitated by CTCF-mediated loops.

Hiraike et al. identify nuclear factor I-A (NFIA) as a transcriptional regulator of brown fat. NFIA activates cell-type-specific enhancers prior to differentiation and facilitates PPARγ binding to regulate the brown fat gene program.

Abramson and colleagues show that the coordinated action of several transcriptional regulators, including Irf4, Irf8, Tbx21, Tcf7 and Ctcfl, acts on medullary-thymic-epithelial-cell-specific accessible regions in the locus encoding the transcriptional regulator Aire to control its expression.

Interactions between chromatin and nuclear components and whether these interactions affect development is not well understood. Here the authors show inner nuclear protein Matrin-3 (Matr3) loss leads to accelerated erythroid maturation, and that Matr3 is involved in chromosomal structure organization and compartmentalization to negatively regulate cell differentiation.

Douglas Higgs and colleagues functionally test the α-globin super-enhancer in mice by genetically deleting its constituent enhancers. They find that the individual regulatory elements seem to act independently and in an additive way with respect to hematological phenotype, gene expression, and chromatin structure and conformation.

Integrating methods that assess allele-specific regulatory activity and chromatin accessibility in T cells identifies putative causal variants for five autoimmune diseases.

Application of SuRE reporter technology to survey the effect of 5.9 million SNPs in the human genome on enhancer and promoter activity identifies over 30,000 SNPs that alter the activity of putative regulatory elements.

Non-genetic malignant clonal dominance is a cell-intrinsic and heritable property that underpins clonal output and response to therapy in cancer. 

Ludwig et al. map transcription and chromatin accessibility in single cells across the brainstem dorsal vagal complex, thereby identifying neuronal populations, including some that control feeding.

Genomic analyses applied to 14 childhood- and adult-onset psychiatric disorders identifies five underlying genomic factors that explain the majority of the genetic variance of the individual disorders.

Exhausted cytotoxic T lymphocytes (CTLs) express the receptor PD-1 as a key signature. Haining and colleagues show that there are different ‘depths’ of exhaustion with a subset of exhausted CTLs that retain polyfunctionality and are responsive to PD-1 blockade.

Quantification of genomic responses to environmental stimuli by current genome-scale assays is limited to indirect measurements or requires knowledge of the transcription factors involved. Here, the authors use genome-wide high-throughput reporter assays to agnostically map enhancer activity in response to glucocorticoid treatment across the human genome.

Human pluripotent cells (hPSCs) in standard culture are similar to mouse epiblast cells, but heterogeneity within hPSC cultures complicates comparisons. Here the authors show that a subpopulation of hPSCs enriched for self-renewal capacity have distinct cell cycle, metabolic, DNA methylation, and ATAC-seq profiles.

Mapping transcription factors (TFs) occupancy is essential for understanding transcriptional programs. Here the authors use biotinylated knockin alleles of key cardiac TFs (GATA4, NKX2-5, MEF2A, MEF2C, SRF, TBX5, TEAD1) to map their genome-wide occupancy in the fetal and adult mouse heart, providing insight into the cardiac transcriptional regulatory network.

Westermann and colleagues define four subtypes of neuroblastoma based on super-enhancer profiles in primary patient samples, which could be linked to distinct clinical outcomes and cell identity characteristics.

This study uses SMARCA2/4-mutant variants to define catalytic activity–dependent and catalytic activity–independent contributions of the ATPase module to the targeting of BAF and PBAF complexes genome-wide.

Multiple myeloma is frequently characterised by translocation of genes next to the immunoglobulin heavy chain locus. In this study, the authors sequence a large cohort of high risk myeloma samples and find translocations of cMyc to the immunoglobulin heavy chain locus and this is associated with poor prognosis.

Phosphorylation of histone H3.3 at serine 31 by CHK1 is shown to stimulate activity of the acetyltransferase p300 in trans. Depletion of histone H3.3 in embryonic stem cells reduces enhancer acetylation during differentiation.

Tyrosine kinases are promising therapeutic targets in multiple cancer types; however, the formation and selection of tyrosine kinase fusions are not fully understood. Here, the authors develop a genome-wide fusion sequencing platform and identify mechanisms and patterns of fusion formation that have implication for targeted therapy.

Treatment of primary glioblastoma cell lines with epigenetic therapy reactivates transposable elements (TEs). TE-derived transcripts can produce human leukocyte antigen class I-presented antigens, which could potentially be therapeutically targeted.

Unstable transcripts like enhancer RNAs are common in vertebrates. McDonald et al. show that such unstable transcripts are rare in plants and that promoters can function as potent enhancers, suggesting diverse cis-regulatory mechanisms in eukaryotes.

A genome-wide association study identifies 17 genetic loci that are associated with the risk of myeloproliferative neoplasms (MPNs), and shows that the modulation of haematopoietic stem cell function drives MPN risk.

An integrative three-dimensional genomic and transcriptional profiling of four human neural cell types links regulatory elements to their target genes and elucidates the function of noncoding variants in neuropsychiatric disorders.

Analysis of 3D chromatin architecture in T-ALL identifies differences in intra-TAD interactions and TAD boundary insulation. Inhibition of oncogenic signal transduction or epigenetic regulation can alter specific 3D interactions.

MAbID offers a multiplexing approach to uncover the genomic distributions of various epigenetic markers, enabling the study of how these markers jointly direct gene expression.

Single-nucleus RNA-sequencing and chromatin-accessibility analyses in rice (a C₃ plant) and sorghum (a C₄ plant) provide insight into how C₄ photosynthesis evolved in bundle-sheath cells, revealing that the acquisition of ancestral cis-elements was key.

Immunoglobulin G (IgG) is the main isotype of antibody in human blood. Here the authors describe 14 genetic variants that affect IgG levels in blood. The data provide new insight into the regulation of humoral immunity that could be useful in the development of antibody-based therapeutics.

While the role of ASLX1 in haematopoiesis and leukaemia has been heavily studied, the role of ASLX2 is unclear. Here the authors show that ASLX2 is required for normal haematopoietic stem cell self-renewal whereas Asxl2 loss promotes leukemogenesis, thus explaining the frequently observed mutations in AML patients

Notch signalling plays a key role in cell fate transitions, but how Notch activates distinct regulatory networks in closely related cell types is not well understood. Here the authors profile Notch and RBPJ targets in the developing mouse cortex and reveal how transcription factor occupancy and chromatin remodelling interact to direct differential gene expression during differentiation.

A Stereo-seq and scRNA-seq atlas of mouse liver in homeostasis and regeneration after partial hepatectomy identifies zonated genes, pathways, cell–cell interactions and gene regulatory networks. Functional validation finds that cooperation between TBL1XR1 and β-catenin activates hepatocyte proliferation.

A set of five small molecules can induce the transformation of fibroblasts into rod photoreceptor-like cells, which can partially restore pupil reflex and visual function when transplanted into a rod degeneration mouse model.

Genetically engineered T cells that induced remission in a patient with chronic lymphocytic leukaemia were found to have disruption of the TET2 gene, which caused T cell changes that potentiated their anti-tumour effects.