Developmental Gene Expression Research Articles

The role of the Polybromo-associated BAF complex in development.

Chromatin is dynamically regulated during development, where structural changes affect the transcription of genes required to promote different cell types. One of the chromatin regulatory factors responsible for transcriptional regulation during development is the SWItch/Sucrose Non-Fermentable (SWI/SNF) complex, an ATP-dependent chromatin remodeling factor conserved throughout eukaryotes. The catalytic subunit of this complex, BRG1, is shared in all three SWI/SNF complexes subfamilies and is essential for developing most cell lineages. Interestingly, many human developmental diseases have correlative or causative mutations in different SWI/SNF subunits. Many polybromo-associated BAF (pBAF) complex-specific subunit genetic alterations result in developmental failures in tissue-specific ways. This observation suggests that the pBAF complex plays a vital role in development and differentiation, and studying the pBAF complex may provide an opportunity to better understand gene regulation during development. In this mini-view, we will focus on the functions of pBAF-specific subunits and their influence on the development of various cell and tissue types by regulating developmental gene expression.

MicroRNA-mediated network redundancy is constrained by purifying selection and contributes to expression robustness in Drosophila melanogaster

MicroRNAs (miRNAs) are post-transcriptional, non-coding regulatory RNAs that function coordinately with transcription factors (TFs) in gene regulatory networks. TFs and their targets are often co-regulated by miRNAs, forming composite feedforward circuits (cFFCs) with varying degrees of redundancy, primarily mediated by miRNAs. However, the maintenance of miRNA-mediated regulatory redundancy and its impact on gene expression evolution remain elusive. By integrating ChIP-seq data from ENCODE and miRNA targeting from TargetScanFly, we quantified miRNA-mediated cFFC redundancy in Drosophila melanogaster embryos and larvae, revealing more than three quarters of miRNA targets are involved in redundant cFFCs. Higher cFFC redundancy, where more miRNAs target the same gene within a cFFC, is correlated with stronger purifying selection, reduced expression divergence between species, and increased expression stability under heat shock stress. Redundant cFFCs primarily regulate older or broadly expressed young genes. These findings highlight the role of miRNA-mediated cFFC redundancy in enhancing gene expression robustness through natural selection.

A Novel Solid Media-Free In-Planta Soybean (Glycine max. (L) Merr.) Transformation Approach

Soybean’s lengthy protocols for transgenic plant production are a bottleneck in the transgenic breeding of this crop. Explants cultured on a medium for an extended duration exhibit unanticipated modifications. Stress-induced somaclonal variations and in vitro contaminations also cause substantial losses of transgenic plants. This effect could potentially be mitigated by direct shoot regeneration without solid media or in-planta transformation. The current study focused primarily on developing a rapid and effective media-free in-planta transformation technique for three soybean genotypes (Wm82) and our newly developed two hybrids, designated as ZX-16 and ZX-3. The whole procedure for a transgenic plant takes the same time as a stable grown seedling. Multiple axillary shoots were regenerated on stable-grown soybean seedlings without the ectopic expression of developmental regulatory genes. An approximate amount of 200 µL medium with a growth regulator was employed for shoot organogenesis and growth. The maximal shoot regeneration percentages in the Wm82 and ZX-3 genotypes were 87.1% and 84.5%, respectively. The stable transformation ranged from 3% to 8.0%, with an average of 5.5%. This approach seems to be the opposite of the hairy root transformation method, which allowed transgenic shoots to be regenerated on normal roots. Further improvement regarding an increase in the transformation efficiency and of this technique for a broad range of soybean genotypes and other dicot species would be extremely beneficial in achieving increased stable transformation.

Spotlight on the function and trends on Extrachromosomal circular DNA (eccDNA) : A bibliometric analysis from 2008-2023.

Extrachromosomal circular DNA (eccDNA),a type of circular DNA that has a nucleosomal structure, is widely distributed in eukaryotic chromosomes and has been found to modulate genome instability and plasticity, playing a role in regulating gene expression and genome evolution. To comprehensively outline the stages of eccDNA research development, including author collaborations, research topics and hotspots, and their temporal evolution trends, we conducted a bibliometric analysis of 242 publications related to eccDNA research published from 2008-2023 in the Web of Science Core Collection. The bibliometric analysis was performed using CiteSpace, the R package Bibliometrix, and VOSviewer. The USA, the University of California system, and Turner Km were found to be the most influential nation, organization, and author in this field, respectively. The exploration of Characterization and Diagnosis, Heterochromatin,Circ-Seq and Cancer Drug Resistance on eccDNA are the most concerned hotspots. EccDNA research has become a rapidly growing hotspot, receiving extensive attention from scholars in recent years. This study is the first to investigate the development and current challenges of eccDNA research through bibliometric analysis.The research on eccDNA has advanced from disorder to more intricate molecular functions. At present, the rapid growth of eccDNA studies in cancer has not been accompanied by an intuitive analysis of its evolutionary patterns. This review provides an overview of eccDNA's biological characteristics and functions, with a focus on its role in cancer research.

MLL oncoprotein levels influence leukemia lineage identities

Chromosomal translocations involving the mixed-lineage leukemia (MLL) locus generate potent oncogenic fusion proteins (oncoproteins) that disrupt regulation of developmental gene expression. By profiling the oncoprotein-target sites of 36 broadly representative MLL-rearranged leukemia samples, including three samples that underwent a lymphoid-to-myeloid lineage-switching event in response to therapy, we find the genomic enrichment of the oncoprotein is highly variable between samples and subject to dynamic regulation. At high levels of expression, the oncoproteins preferentially activate either an acute lymphoblastic leukemia (ALL) program, enriched for pro-B-cell genes, or an acute myeloid leukemia (AML) program, enriched for hematopoietic-stem-cell genes. The fusion-partner-specific-binding patterns over these gene sets are highly correlated with the prevalence of each mutation in ALL versus AML. In lineage-switching samples the oncoprotein levels are reduced and the oncoproteins preferentially activate granulocyte-monocyte progenitor (GMP) genes. In a sample that lineage switched during treatment with the menin inhibitor revumenib, the oncoprotein and menin are reduced to undetectable levels, but ENL, a transcriptional cofactor of the oncoprotein, persists on numerous oncoprotein-target loci, including genes in the GMP-like lineage-switching program. We propose MLL oncoproteins promote lineage-switching events through dynamic chromatin binding at lineage-specific target genes, and may support resistance to menin inhibitors through similar changes in chromatin occupancy.

Transcriptional pathways of terminal differentiation in high- and low-density blood granulocytes in sepsis

BackgroundTrauma and infection induce emergency granulopoiesis. Counts of immature granulocytes and transcriptional pathways of terminal granulocytic differentiation in blood are elevated in sepsis but correlate with disease severity. This limits their performance as sepsis biomarkers in critically ill patients. We hypothesized that activation of these pathways in sepsis is attributable to immature low-density (LD) rather than mature high-density (HD) granulocytes.MethodsWe included patients with sepsis and systemic inflammatory response syndrome (SIRS) of comparable disease severity, and additionally septic shock, on intensive or intermediate care unit admission. Blood granulocyte isolation by CD15 MicroBeads was followed by density-gradient centrifugation. Flow cytometry was used to determine counts of developmental stages (precursors) and their relative abundancies in total, HD, and LD granulocytes. Five degranulation markers were quantified in plasma by multiplex immunoassays. A set of 135 genes mapping granulocyte differentiation was assayed by QuantiGene™ Plex. CEACAM4, PLAC8, and CD63 were analyzed by qRT-PCR. Nonparametric statistical tests were applied.ResultsPrecursor counts appeared higher in sepsis than SIRS but did not correlate with disease severity for early immature and mature granulocytes. Precursor subpopulations were enriched at least ten-fold in LD over HD granulocytes without sepsis-SIRS differences. Degranulation markers in blood were comparable in sepsis and SIRS. Higher expression of early developmental genes in sepsis than SIRS was more pronounced in LD and less in HD than total granulocytes. Only the cell membrane protein encoding genes CXCR2 and CEACAM4 were more highly expressed in SIRS than sepsis. By qRT-PCR, the azurophilic granule genes CD63 and PLAC8 showed higher sepsis than SIRS levels in LD granulocytes and PLAC8 also in total granulocytes where its discriminatory performance resembled C-reactive protein (CRP).ConclusionsTranscriptional programs of early terminal granulocytic differentiation distinguish sepsis from SIRS due to both higher counts of immature granulocytes and elevated expression of early developmental genes in sepsis. The sustained expression of PLAC8 in mature granulocytes likely accounts for its selection in the whole blood SeptiCyte™ LAB test. Total granulocyte PLAC8 rivals CRP as sepsis biomarker. However, infection-specific transcriptional pathways, that differentiate sepsis from sterile stress-induced granulocytosis more reliably than CRP, remain to be identified.

Stabilizing selection and adaptation shape cis and trans gene expression variation in C. elegans.

An outstanding question in the evolution of gene expression is the relative influence of neutral processes versus natural selection, including adaptive change driven by directional selection as well as stabilizing selection, which may include compensatory dynamics. These forces shape patterns of gene expression variation within and between species, including the regulatory mechanisms governing expression in cis and trans . In this study, we interrogate intraspecific gene expression variation among seven wild C. elegans strains, with varying degrees of genomic divergence from the reference strain N2, leveraging this system's unique advantages to comprehensively evaluate gene expression evolution. By capturing allele-specific and between-strain changes in expression, we characterize the regulatory architecture and inheritance mode of gene expression variation within C. elegans and assess their relationship to nucleotide diversity, genome evolutionary history, gene essentiality, and other biological factors. We conclude that stabilizing selection is a dominant influence in maintaining expression phenotypes within the species, and the discovery that genes with higher overall expression tend to exhibit fewer expression differences supports this conclusion, as do widespread instances of cis differences compensated in trans . Moreover, analyses of human expression data replicate our finding that higher expression genes have less variable expression. We also observe evidence for directional selection driving expression divergence, and that expression divergence accelerates with increasing genomic divergence. To provide community access to the data from this first analysis of allele-specific expression in C. elegans , we introduce an interactive web application, where users can submit gene-specific queries to view expression, regulatory pattern, inheritance mode, and other information: https://wildworm.biosci.gatech.edu/ase/ .

Evolution and Plasticity of Gene Expression Under Progressive Warming in Drosophila subobscura.

Understanding the molecular mechanisms of thermal adaptation is crucial to predict the impacts of global warming. However, there is still a lack of research on the effects of rising temperatures over time and of studies involving different populations from the same species. The present study focuses on these two aspects, which are of great importance in understanding how organisms cope and adapt to ongoing changes in their environment. This study investigates the impact of global warming on the gene expression patterns of Drosophila subobscura populations from two different latitudinal locations after 23 generations of evolution. Our results indicate that evolutionary changes depend on the genetic background of the populations, with different starting points for thermal evolution, and that high-latitude populations show more pronounced evolutionary changes, with some evidence of convergence towards low-latitude populations. We found an interplay between plasticity and selection, with the high-latitude population showing fewer initial plastic genes and lower levels of adaptive plasticity, but a greater magnitude of change in both plastic and selective responses during evolution under warming conditions compared with its low-latitude counterpart. A substantial proportion of the transcriptome was observed to be evolving, despite the lack of observable response at higher-order phenotypic traits. The interplay between plasticity and selection may prove to be an essential component in shaping species' evolutionary responses to climate change. Furthermore, the value of conducting studies on multiple populations of the same species is emphasised, given the identification of differences between populations with different backgrounds in several contexts.

Molecular states underlying neuronal cell type development and plasticity in the whisker cortex.

A single-nucleus transcriptomic atlas of the whisker somatosensory cortex (wS1) during early postnatal developmentDifferent neuronal subclasses in wS1 show distinct developmental gene expression changesThe composition of L2/3 glutamatergic neurons changes between the second and the third postnatal weekDevelopmental gene expression and cell type changes are conserved between wS1 and the primary visual cortex (V1)Unlike V1, these changes are not affected by prolonged sensory deprivationBrief whisker deprivation induces subclass-specific activity-dependent gene expression in a whisker column-specific fashion.

Dietary supplementation with thymoquinone inhibits rotenone induced developmental toxicity in Drosophila melanogaster: Focus on ovary and larval development

Pesticide exposure has been associated with various health conditions like asthma, Parkinson’s disease, Alzheimer’s disease, genetic disorders, epigenetic changes, oxidative stress, and hormonal disruption. Recent evidence suggests that infants are more vulnerable to pesticides (such as rotenone) than adults. Although the disease has already been clinically characterized, no treatment has yet been developed to improve pathology or prevent developmental toxicity. Therefore, the purpose of this study was to investigate whether thymoquinone (TQ) from Nigella sativa seeds could ameliorate rotenone (ROT)-induced developmental damage in both Drosophila melanogaster ovary and third instar larvae. Female adult wild-type flies and third instar larvae (72 ± 2 h after egg laying) were exposed to ROT and/or TQ through food for 48 and 24 h respectively. Results indicate that co-exposure of TQ inhibits ROT-induced increased oxidative stress and alleviates abnormal antioxidant enzyme activities. Further, TQ alters developmental gene expression (Bacoid, Oscar, Nanos, and Gurken), impedes mitochondrial dysfunction, and reduces apoptosis in ROT induced ovary. In addition, TQ changes ROT induced abnormal crawling behaviour, cholinergic dysfunction, and dopamine depletion to normal levels in third instar larvae. Also, TQ reduces pupation and emergence time in ROT induced third instar larvae. The above findings demonstrate that ROT exposure during early developmental stages is inevitable, and TQ supplementation prevents developmental toxicity in the Drosophila ovary and third instar larvae. A diet enriched TQ provides a ray of hope in preventing ROT induced developmental toxicity.

Single-Cell Transcriptomics Tracking the Evolution of Cell and Gene Expression in Blood and Urine Cells of a Patient with IgA Nephropathy before, during, and after Therapy

Single-Cell Transcriptomics Tracking the Evolution of Cell and Gene Expression in Blood and Urine Cells of a Patient with IgA Nephropathy before, during, and after Therapy

Protective role of ghrelin against 6PPD-quinone-induced neurotoxicity in zebrafish larvae (Danio rerio) via the GHSR pathway

The toxicity mechanisms of N-(1,3-dimethylbutyl)-N′-phenyl-p-phenylenediamine quinone (6PPD-Q), an antioxidant derivative of 6PPD via ozone reaction commonly used in rubber and tire industries, were investigated in zebrafish larvae with concentrations ranging from 0 to 50 μg/L. Despite normal hatchability, 6PPD-Q exposure led to reduced body length and swimming distance in 120 hours post-fertilization (hpf) larvae. At the highest concentration (50 μg/L), 6PPD-Q significantly impaired dopaminergic neuron development and neurotransmitter levels, including dopamine, 5-hydroxytryptamine, and glutamate. Transcriptome profiling unveiled perturbations in growth and developmental gene expression, such as upregulation of runx2a, runx2b, and ghrl (ghrelin and obestatin prepropeptide), and downregulation of stat1b, auto1, and cidea. Notably, anamorelin, a growth hormone secretagogue receptor (GHSR) agonist, recovered the behavioral deficits induced by 6PPD-Q, implying a neuroprotective role of ghrelin possibly mediated via the ghrelin/GHSR pathway. Collectively, our findings indicate that ghrelin upregulation may counteract 6PPD-Q toxicity in zebrafish larvae, shedding light on potential therapeutic avenues for mitigating the adverse effects of this antioxidant byproduct.

A high-throughput gene expression analysis software tool for developmental time series and gene signature analysis of human cardiomyocyte differentiation

Publicly available high-throughput gene expression data enable the investigation of biological processes by the scientific community. Although several bioinformatics tools offer methodologies for basic differential gene expression analysis, difficulties arise in the analysis of multiple sample groups comprising a developmental time series, especially when the identification and classification of unique gene expression patterns is the primary goal of the study. Data analysis using these tools requires programming experience, which limits the accessibility of these tools to the broader community. To streamline developmental time-series investigations, we created the Developmental Gene Expression Analysis (devGEA) tool. This environment can be implemented locally or via web browsers to expedite differential gene expression analysis. This tool provides gene signature determination methods that can classify differentially expressed genes based on their correlation with gene expression patterns. devGEA was used to characterize cardiac development gene expression signatures from high-throughput RNA-seq datasets profiling small-molecule directed cardiomyocyte differentiation of human pluripotent stem cell lines (hiPSCs). After pre-processing, discrete gene expression criteria-based expected changes were used to classify the genes into developmental signatures. Several cardiomyocyte differentiation markers and candidate cardiac genes representing different developmental signatures were experimentally validated using the GIBCOTM hiPSC line. This method was then compared to a gene signature correlation approach that classified expressed genes based on their degree of similarity with key cardiac developmental signatures representing the stages of cardiomyocyte differentiation. Therefore, devGEA provides a robust workflow for investigator-driven analysis of developmental time series, allowing for the identification of differentially expressed genes and gene signatures for extensive experimental investigation. We also introduced a method for classifying genes by their correlation with genes or developmental patterns of interest. Our correlation-based method takes advantage of a priori knowledge of an experiment and is conceptually simpler than unsupervised clustering approaches.

Regional patterns of human cortex development correlate with underlying neurobiology

Human brain morphology undergoes complex changes over the lifespan. Despite recent progress in tracking brain development via normative models, current knowledge of underlying biological mechanisms is highly limited. We demonstrate that human cortical thickness development and aging trajectories unfold along patterns of molecular and cellular brain organization, traceable from population-level to individual developmental trajectories. During childhood and adolescence, cortex-wide spatial distributions of dopaminergic receptors, inhibitory neurons, glial cell populations, and brain-metabolic features explain up to 50% of the variance associated with a lifespan model of regional cortical thickness trajectories. In contrast, modeled cortical thickness change patterns during adulthood are best explained by cholinergic and glutamatergic neurotransmitter receptor and transporter distributions. These relationships are supported by developmental gene expression trajectories and translate to individual longitudinal data from over 8000 adolescents, explaining up to 59% of developmental change at cohort- and 18% at single-subject level. Integrating neurobiological brain atlases with normative modeling and population neuroimaging provides a biologically meaningful path to understand brain development and aging in living humans.

Design the fusion double-strand RNAs to control two global sap-sucking pests

RNA interference (RNAi) is an effective pest management strategy through silencing the crucial genes in target organisms. However, the effectiveness of targeting a single gene is often limited by the silencing efficiency due to tissue or developmental stage-specific gene expression. Moreover, multiple pests often infest the same crop simultaneously under current ecological conditions. Therefore, a combined strategy of “targeting multiple genes” and “controlling multiple pests” is expected to yield better management results. In this study, homologous genes from two globally sap-sucking pests, the peach aphid (Myzus persicae) and the whitefly (Bemisia tabaci), were screened on a genome-wide scale. Subsequently, RNAi bioassays showed silencing the genes (MpAbd-A, MpH3, MpRpL27a, and MpScr) exhibited high mortalities in both species, which were further selected for designing fusion dsRNAs. These fusion dsRNAs resulted in higher mortalities in both pests than single gene silencing and posed a minimal off-target risk to the predator ladybeetle (Propylaea japonica) based on the sequence analysis. Finally, the tobacco plants expressing the fusion dsRNAs through virus-induced gene silencing (VIGS) technology enhanced the resistance to both pests. In conclusion, this study proposes a novel RNAi-based approach for managing two sap-sucking pests simultaneously.

Genomic factors shaping codon usage across the Saccharomycotina subphylum.

Codon usage bias, or the unequal use of synonymous codons, is observed across genes, genomes, and between species. It has been implicated in many cellular functions, such as translation dynamics and transcript stability, but can also be shaped by neutral forces. We characterized codon usage across 1,154 strains from 1,051 species from the fungal subphylum Saccharomycotina to gain insight into the biases, molecular mechanisms, evolution, and genomic features contributing to codon usage patterns. We found a general preference for A/T-ending codons and correlations between codon usage bias, GC content, and tRNA-ome size. Codon usage bias is distinct between the 12 orders to such a degree that yeasts can be classified with an accuracy greater than 90% using a machine-learning algorithm. We also characterized the degree to which codon usage bias is impacted by translational selection. We found it was influenced by a combination of features, including the number of coding sequences, BUSCO count, and genome length. Our analysis also revealed an extreme bias in codon usage in the Saccharomycodales associated with a lack of predicted arginine tRNAs that decode CGN codons, leaving only the AGN codons to encode arginine. Analysis of Saccharomycodales gene expression, tRNA sequences, and codon evolution suggests that avoidance of the CGN codons is associated with a decline in arginine tRNA function. Consistent with previous findings, codon usage bias within the Saccharomycotina is shaped by genomic features and GC bias. However, we find cases of extreme codon usage preference and avoidance along yeast lineages, suggesting additional forces may be shaping the evolution of specific codons.

Translational Regulation of Duplicated Gene Expression Evolution in Allopolyploid Cotton.

Polyploidy, a prevalent event in plant evolution, drives phenotypic diversification and speciation. While transcriptional changes and regulation in polyploids have been extensively studied, the translational level impact remains largely unexplored. To address this gap, we conducted a comparative transcriptomic and translatomic analysis of cotton leaves from allopolyploid species G. hirsutum (AD1) and G. barbadense (AD2) relative to their model A-genome and D-genome diploid progenitors. Our data revealed that while allopolyploidization significantly affects the transcriptional landscape, its impact on translation was relatively modest, evidenced by a narrower expression range and fewer expression changes in ribosome-protected fragments than in mRNA levels. Allopolyploid-specific changes commonly identified in both AD1 and AD2 were observed in 7393 genes at either transcriptional or translational levels. Interestingly, the majority of translational changes exhibited concordant down-regulation in both ribosome-protected fragments and mRNA, particularly associated with terpenoid synthesis and metabolism (352 genes). Regarding translational efficiency (TE), at least one-fifth of cotton genes exhibit translational level regulation, with a general trend of more down-regulation (13.9-15.1%) than up-regulation (7.3-11.2%) of TE. The magnitude of translational regulation was slightly reduced in allopolyploids compared with diploids, and allopolyploidy tends to have a more profound impact on genes and functional associations with ultra-low TE. Moreover, we demonstrated a reduced extent of homeolog expression biases during translation compared with transcription. Our study provides insights into the regulatory consequences of allopolyploidy post-transcription, contributing to a comprehensive understanding of regulatory mechanisms of duplicated gene expression evolution.

Cooperative insulation of regulatory domains by CTCF-dependent physical insulation and promoter competition

The specificity of gene expression during development requires the insulation of regulatory domains to avoid inappropriate enhancer-gene interactions. In vertebrates, this insulator function is mostly attributed to clusters of CTCF sites located at topologically associating domain (TAD) boundaries. However, TAD boundaries allow some physical crosstalk across regulatory domains, which is at odds with the specific and precise expression of developmental genes. Here we show that developmental genes and nearby clusters of CTCF sites cooperatively foster the robust insulation of regulatory domains. By genetically dissecting a couple of representative loci in mouse embryonic stem cells, we show that CTCF sites prevent undesirable enhancer-gene contacts (i.e. physical insulation), while developmental genes preferentially contribute to regulatory insulation through non-structural mechanisms involving promoter competition rather than enhancer blocking. Overall, our work provides important insights into the insulation of regulatory domains, which in turn might help interpreting the pathological consequences of certain structural variants.

Comparative Transcriptome Analysis Reveals Differential Cutaneous Gene Expression in the Color Variation of Two Ornamental Discus, Red Melon and Red Cover.

Red Melon (RM) and Red Cover (RC) discus (Symphysodon spp.) are ornamental fish varieties that were selectively bred from the wild parental lineages of the brown discus S. aquafaciatus over many generations, resulting in distinct cutaneous patterns from juveniles to adults. To better understand the underlying mechanisms, skin samples were collected from juveniles aged 60 days and adults aged 1 year from RM and RC for investigations. Microscopic observation detected xanthophores and erythrophores in all samples, except RC juveniles with no erythrophores. Melanophores were presented only in RC. The comparative analysis revealed that genes involved in pteridine synthesis (gch1 and zgc:153031), one-carbon metabolism (aldh1l2 and zgc153031), and lipid metabolism (apoda and klf1) were differentially expressed in RM juveniles, which may be associated with the development of erythrophores and xanthophores. The temporal inhibition of melanophore differentiation and development was observed in RM juveniles, coupled with elevated expression of notum2 and sost, two antagonist genes in Wnt-signaling, suggesting their roles in melanophore development. Distinct pigment pattern between RM and RC since the juvenile stage may be driven by the differential expression of multiple axial developmental genes, including GATA, ankyrin, and mitotic spindle orientation proteins. This is the first report to describe the differential growth of cutaneous pigments and the molecular processes involved in red discus. The results provided valuable insights into pigment pattern differences in an interesting ornamental fish model.

KMT2A oncoproteins induce epigenetic resistance to targeted therapies.

Chromosomal translocations involving the Lysine-Methyl-Transferase-2A ( KMT2A ) locus generate potent oncogenic fusion proteins (oncoproteins) that disrupt regulation of developmental gene expression. By profiling the oncoprotein-target sites of 36 broadly representative KMT2A -rearranged leukemia samples, including three samples that underwent a lymphoid-to-myeloid lineage-switching event in response to therapy, we find the genomic enrichment of the oncoprotein is highly variable between samples and subject to dynamic regulation. At high levels of expression, the oncoproteins preferentially activate either an acute lymphoblastic leukemia (ALL) program, enriched for pro-B-cell genes, or an acute myeloid leukemia (AML) program, enriched for hematopoietic-stem-cell genes. The fusion-partner-specific-binding patterns over these gene sets are highly correlated with the prevalence of each mutation in ALL versus AML. In lineage-switching samples the oncoprotein levels are reduced and the oncoproteins preferentially activate granulocyte-monocyte progenitor (GMP) genes. In a sample that lineage switched during treatment with the menin inhibitor revumenib, the oncoprotein and menin are reduced to undetectable levels, but ENL, a transcriptional cofactor of the oncoprotein, persists on numerous oncoprotein-target loci, including genes in the GMP-like lineage-switching program. We propose KMT2A oncoproteins promote lineage-switching events through dynamic chromatin binding and can induce epigenetic lesions, marked by ENL, that support resistance to targeted therapies.