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PubMed2025

Genome topology analysis and transcriptomics of human osteoclasts reveals enhancer-promoter interactions at loci for bone traits and diseases.

Genome-wide association studies (GWAS) relevant to osteoporosis have identified hundreds of loci; however, understanding how these variants influence the phenotype is complicated because most reside in non-coding DNA sequence that serves as transcriptional enhancers and repressors. To advance knowledge on these regulatory elements in osteoclasts (OCs), we performed Micro-C analysis, which informs on the genome topology of these cells and integrated the results with transcriptome and GWAS data to further define loci linked to BMD. Using blood cells isolated from 4 healthy participants aged 31-61 yr, we cultured OC in vitro and generated a Micro-C chromatin conformation capture dataset. We characterized chromatin loops (CLs) in OC from among more than 69 million chromatin interactions identified in the genome. Of the CL identified in OC, >16 000 were unique compared to precursor cells. When sentinel single nucleotide polymorphisms from osteoporosis and bone-related GWAS and those in linkage disequilibrium at r 2 > 0.6 were mapped to CL for OC, 12 588 of these variants were observed within chromatin contact regions. Notable in differential gene ontology enrichment analyses of the topology data for OC and precursors were pathways regulating pluripotency of stem cells, Wnt signaling, nucleotide-binding oligomerization domain (NOD)-like receptor signaling and chemokine signaling. These data, in combination with other 3D genome architecture and epigenetic data (eg, histone modifications and chromatin accessibility), will be useful in modeling to predict genome-wide, which enhancers regulate which genes in OC. This data will therefore also be informative for resolving GWAS hits. In conclusion, we have generated a high-resolution genome topology dataset for human OC and have used this to identify CLs relevant to studies of the genetics of osteoporosis. This data will serve as a powerful resource to inform future functional studies of OC biology.

BMD↗
PubMed2007

Evolution of duplicate gene expression in polyploid and hybrid plants.

Allopolyploidy is a prominent mode of speciation in flowering plants. On allopolyploidy, genomic changes can take place, including chromosomal rearrangement and changes in gene expression; these processes continue over evolutionary time. Recent studies of gene expression in polyploid and hybrid plants, reviewed here, have examined expression in natural polyploids and synthetic neopolyploids as well as in diploid and F(1) hybrids. Considerable changes in gene expression have been observed in allopolyploids, including up- or downregulation of expression in the polyploids compared with their parents, unequal expression of duplicated genes, and silencing of one copy. Genes in a variety of functional categories show altered expression, and the patterns vary considerably by gene. Some changes seem to be stochastic, whereas others are repeatable. Gene expression changes can be organ specific. Reciprocal silencing of duplicates in different organs has been observed, suggesting subfunctionalization and long-term retention of duplicates. It has become clear that hybridization has a much greater effect than chromosome doubling on gene expression in allopolyploids. Diploid and triploid F(1) hybrids can show alterations of expression levels compared with their parents. Parent-of-origin effects on gene expression have been examined, and loss of gene imprinting has been shown. Some gene expression changes in polyploids and hybrids can be correlated with phenotypic effects. Demonstrated mechanisms of gene expression changes include DNA methylation, histone modifications, and antisense RNA. Several hypotheses have been proposed for why gene expression is altered in allopolyploids and hybrids.

Evolution, Molecular↗
PubMed2004

Maternal nutrition and fetal development.

Nutrition is the major intrauterine environmental factor that alters expression of the fetal genome and may have lifelong consequences. This phenomenon, termed "fetal programming," has led to the recent theory of "fetal origins of adult disease." Namely, alterations in fetal nutrition and endocrine status may result in developmental adaptations that permanently change the structure, physiology, and metabolism of the offspring, thereby predisposing individuals to metabolic, endocrine, and cardiovascular diseases in adult life. Animal studies show that both maternal undernutrition and overnutrition reduce placental-fetal blood flows and stunt fetal growth. Impaired placental syntheses of nitric oxide (a major vasodilator and angiogenesis factor) and polyamines (key regulators of DNA and protein synthesis) may provide a unified explanation for intrauterine growth retardation in response to the 2 extremes of nutritional problems with the same pregnancy outcome. There is growing evidence that maternal nutritional status can alter the epigenetic state (stable alterations of gene expression through DNA methylation and histone modifications) of the fetal genome. This may provide a molecular mechanism for the impact of maternal nutrition on both fetal programming and genomic imprinting. Promoting optimal nutrition will not only ensure optimal fetal development, but will also reduce the risk of chronic diseases in adults.

Amino Acids↗
PubMed2006

IFN-beta-induced SOCS-1 negatively regulates CD40 gene expression in macrophages and microglia.

Costimulation between T cells and antigen-presenting cells is required for adaptive immune responses. CD40, a costimulatory molecule, is expressed in macrophages and microglia. The aberrant expression of CD40 is involved in human diseases including multiple sclerosis, rheumatoid arthritis, and Alzheimer's disease. CD40 expression is induced by a variety of stimuli, including IFN-gamma and lipopolysaccharide (LPS). In this study, we describe the molecular basis by which IFN-beta, a cytokine with immunomodulatory properties, regulates CD40 gene expression. IFN-beta induces CD40 expression in macrophages and microglia at the transcriptional level, and GAS elements in the CD40 promoter are required for IFN-beta-induced CD40 promoter activity. The critical role of signal transducers and activators of transcription-1alpha (STAT-1alpha) in this response was confirmed by utilizing primary microglia from STAT-1alpha deficient mice. IFN-beta induces suppressor of cytokine signaling-1 (SOCS-1) gene expression, which inhibits cytokine signaling by inhibiting activation of STAT proteins. The ectopic expression of SOCS-1 abrogates IFN-beta-mediated STAT-1alpha activation and inhibits IFN-beta-induced CD40 expression. IFN-beta-induced recruitment of STAT-1alpha and RNA Pol II and permissive histone modifications on the CD40 promoter are also inhibited by SOCS-1 overexpression. These novel results indicate that IFN-beta-induced SOCS-1 plays an important role in the negative regulation of IFN-beta-induced CD40 gene expression.

Animals↗
PubMed2025

PATTY corrects open chromatin bias for improved bulk and single-cell CUT&Tag profiling.

Precise profiling of epigenomes is essential for better understanding chromatin biology and gene regulation. Cleavage Under Targets & Tagmentation (CUT&Tag) is an efficient epigenomic profiling technique that can be performed on a low number of cells and at the single-cell level. With its growing adoption, CUT&Tag datasets spanning diverse biological systems are rapidly accumulating in the field. CUT&Tag assays use the hyperactive transposase Tn5 for DNA tagmentation. Tn5's preference toward accessible chromatin alters CUT&Tag sequence read distributions in the genome and introduces open chromatin bias that can confound downstream analysis, an issue more substantial in sparse single-cell data. We show that open chromatin bias extensively exists in published CUT&Tag datasets, including those generated with recently optimized high-salt protocols. To address this challenge, we present PATTY (Propensity Analyzer for Tn5 Transposase Yielded bias), a comprehensive computational method that corrects open chromatin bias in CUT&Tag data by leveraging accompanying ATAC-seq. By integrating transcriptomic and epigenomic data using machine learning and integrative modeling, we demonstrate that PATTY enables accurate and robust detection of occupancy sites for both active and repressive histone modifications, including H3K27ac, H3K27me3, and H3K9me3, with experimental validation. We further develop a single-cell CUT&Tag analysis framework built on PATTY and show improved cell clustering when using bias-corrected single-cell CUT&Tag data compared to using uncorrected data. Beyond CUT&Tag, PATTY sets a foundation for further development of bias correction methods for improving data analysis for all Tn5-based high-throughput assays.

Journal Article↗
PubMed2006

The cancer epigenome--components and functional correlates.

It is increasingly apparent that cancer development not only depends on genetic alterations but on an abnormal cellular memory, or epigenetic changes, which convey heritable gene expression patterns critical for neoplastic initiation and progression. These aberrant epigenetic mechanisms are manifest in both global changes in chromatin packaging and in localized gene promoter changes that influence the transcription of genes important to the cancer process. An exciting emerging theme is that an understanding of stem cell chromatin control of gene expression, including relationships between histone modifications and DNA methylation, may hold a key to understanding the origins of cancer epigenetic changes. This possibility, coupled with the reversible nature of epigenetics, has enormous significance for the prevention and control of cancer.

Animals↗
PubMed2002

Comparative sequence analysis of the X-inactivation center region in mouse, human, and bovine.

We have sequenced to high levels of accuracy 714-kb and 233-kb regions of the mouse and bovine X-inactivation centers (Xic), respectively, centered on the Xist gene. This has provided the basis for a fully annotated comparative analysis of the mouse Xic with the 2.3-Mb orthologous region in human and has allowed a three-way species comparison of the core central region, including the Xist gene. These comparisons have revealed conserved genes, both coding and noncoding, conserved CpG islands and, more surprisingly, conserved pseudogenes. The distribution of repeated elements, especially LINE repeats, in the mouse Xic region when compared to the rest of the genome does not support the hypothesis of a role for these repeat elements in the spreading of X inactivation. Interestingly, an asymmetric distribution of LINE elements on the two DNA strands was observed in the three species, not only within introns but also in intergenic regions. This feature is suggestive of important transcriptional activity within these intergenic regions. In silico prediction followed by experimental analysis has allowed four new genes, Cnbp2, Ftx, Jpx, and Ppnx, to be identified and novel, widespread, complex, and apparently noncoding transcriptional activity to be characterized in a region 5' of Xist that was recently shown to attract histone modification early after the onset of X inactivation.

Animals↗
PubMed2026

Identification of genomic features that uniquely impact estrogen receptor alpha binding and its effects on gene expression in endometrial cancer.

Estrogen receptor 1 (ESR1, also known as estrogen receptor alpha or ER) is an established oncogenic transcription factor in breast and endometrial cancer; however, more is known about the mechanisms controlling ER behavior in breast cancer, and therapies targeting ER have been much more successful in breast cancer. To address this disparity, we characterize the genomic features that control ER in endometrial cancer and determine to what extent these factors differ from those in breast cancer. We focus on the locations of estrogen response elements (EREs), ER's preferred DNA-binding motif, throughout the human genome. To identify factors that predict ER genomic binding and effects on target gene expression, we apply machine learning to genomic data for each ERE in Ishikawa cells (ER-positive endometrial cancer) and T-47D cells (ER-positive breast cancer). Many of these factors, such as chromatin accessibility and histone modifications, are predictive of ER activity in both cell lines. However, the transcription factors that predict ER activity are cell type specific, including FOXA1 and GATA3 in T-47D cells and ETV4 and SOX17 in Ishikawa cells. In addition, the features that predict ER binding and effects on gene expression differ, with transcription at EREs in the absence of estrogen being predictive of ER regulatory activity. A CRISPR knockout screen in Ishikawa cells, as well as follow-up experiments, confirms the discovery that SOX17 controls ER activity in endometrial cancer cells. These results identify important genomic features of ER binding and regulatory activity and how these features differ between endometrial cancer and breast cancer cells.

Humans↗
PubMed2026

Genome-wide survey of spliceosomal snRNA transcripts across hundreds of human biosamples reveals abundant transcription but low maturation level of snRNA variants.

Small nuclear RNAs (snRNAs) are essential components of the spliceosome and are encoded by large, multicopy gene families. However, their genome-wide identification and quantification have remained challenging due to high sequence similarity among family members. To address this, we utilized RAMPAGE (Rapid Amplification of cDNA Ends) data from the ENCODE project to comprehensively profile nascent transcription of spliceosomal snRNAs across 115 human biosamples. We identified 74 expressed snRNA variants, characterized by canonical promoter features including bidirectional transcription flanking a positioned nucleosome, active histone modifications, and evolutionary conservation- features largely absent from unexpressed variants. These transcriptional events were corroborated by total RNA-seq and Bru-seq data, yet the majority of these variants showed extremely low levels in small RNA-seq, indicating post-transcriptional bottlenecks for snRNA processing and maturation. Our findings reveal new layers of regulation in snRNA variant expression and suggest that selective post-transcriptional processing plays a critical role in shaping the functional snRNA repertoire and its contribution to splicing regulation.

Journal Article↗
PubMed2026

Analyzing Meiosis in Maize.

Meiosis is central to sexual reproduction and the main source of genetic diversity in plants. Understanding how meiotic processes are regulated has direct relevance to agriculture. As meiotic recombination is the vehicle of plant breeding, gaining the ability to influence recombination patterns can accelerate crop improvement. Maize is a powerful model for studying plant meiosis, thanks to its large chromosomes, well-developed genetics, and the availability of diverse cytogenetic and molecular tools. Insights gained from maize studies can extend to other species. In this review, we describe a variety of approaches for examining meiosis and meiotic recombination in maize. Cytological techniques, including protein immunolocalization and fluorescence in situ hybridization (FISH), enable visualization of chromosome structure and behavior, as well as crossover (CO) formation. Chromatin immunoprecipitation (ChIP) is used in meiosis research to determine locations of recombination proteins, identify recombination sites, and elucidate chromatin features, such as histone modifications. Quantification of COs at specific genomic sites through pollen typing by droplet digital PCR allows precise high-resolution measurement of recombination rates. Combining cytology, protein localization, and molecular assays provides a multiscale picture of meiosis, linking molecular mechanisms to chromosome behavior and, ultimately, to genetic variation.

Journal Article↗
PubMed2004

Divergent roles of a pair of homologous jumonji/zinc-finger-class transcription factor proteins in the regulation of Arabidopsis flowering time.

Flowering in Arabidopsis thaliana is controlled by multiple pathways, including the photoperiod pathway and the FLOWERING LOCUS C (FLC)-dependent pathway. Here, we report that a pair of related jumonji-class transcription factors, EARLY FLOWERING 6 (ELF6) and RELATIVE OF EARLY FLOWERING 6 (REF6), play divergent roles in the regulation of Arabidopsis flowering. ELF6 acts as a repressor in the photoperiod pathway, whereas REF6, which has the highest similarity to ELF6, is an FLC repressor. Ectopic expression studies and expression pattern analyses show that ELF6 and REF6 have different cellular roles and are also regulated differentially despite their sequence similarities. Repression of FLC expression by REF6 accompanies histone modifications in FLC chromatin, indicating that the transcriptional regulatory activity of this class of proteins includes chromatin remodeling. This report demonstrates the in vivo functions of this class of proteins in higher eukaryotes.

Amino Acid Sequence↗
PubMed2006

A comprehensive structure-function analysis of Arabidopsis SNI1 defines essential regions and transcriptional repressor activity.

The expression of systemic acquired resistance (SAR) in plants involves the upregulation of many Pathogenesis-Related (PR) genes, which work in concert to confer resistance to a broad spectrum of pathogens. Because SAR is a costly process, SAR-associated transcription must be tightly regulated. Arabidopsis thaliana SNI1 (for Suppressor of NPR1, Inducible) is a negative regulator of SAR required to dampen the basal expression of PR genes. Whole genome transcriptional profiling showed that in the sni1 mutant, Nonexpresser of PR genes (NPR1)-dependent benzothiadiazole S-methylester-responsive genes were specifically derepressed. Interestingly, SNI1 also repressed transcription when expressed in yeast, suggesting that it functions as an active transcriptional repressor through a highly conserved mechanism. Chromatin immunoprecipitation indicated that histone modification may be involved in SNI1-mediated repression. Sequence comparison with orthologs in other plant species and a saturating NAAIRS-scanning mutagenesis of SNI1 identified regions in SNI1 that are required for its activity. The structural similarity of SNI1 to Armadillo repeat proteins implies that SNI1 may form a scaffold for interaction with proteins that modulate transcription.

Amino Acid Sequence↗
PubMed2026

Epigenetics and In Silico Transcriptome Analysis of Pediatric Acute Myeloid Leukemia.

Pediatric acute myeloid leukemia (AML) is a heterogeneous hematologic malignancy that accounts for about 15%-20% of childhood leukemias. Despite therapeutic advances, relapses remain common, and survival for high-risk patients is below 60%. Unlike adult AML, pediatric AML displays distinct genetic mutations, including FLT3-ITD, NPM1, KMT2A rearrangements, and core-binding factors (CBF) fusions, as well as extensive epigenetic dysregulation. Aberrant DNA methylation, histone modifications, and altered non-coding RNA expressions disrupt hematopoietic differentiation and activate oncogenic transcriptional networks. Recent advances in silico transcriptomic analysis have transformed the study of pediatric AML by integrating gene expression and epigenetic data to identify molecular drivers and regulatory networks. Computational RNA-seq pipelines and pathway analyses have highlighted key epigenetic regulators, including DNMT3A, TET2, and HDACs, as potential therapeutic targets. Multi-omics approaches combining transcriptomic, methylomic, and chromatin accessibility data are increasingly used to define biomarkers for diagnosis, prognosis, and therapeutic response. This review provides a comprehensive overview of the molecular and epigenetic landscape of pediatric AML, emphasizing the power of in silico transcriptome analysis to uncover disease mechanisms, refine patient stratification, and guide the development of precision-based epigenetic therapies aimed at improving long-term outcomes in children with AML.

Humans↗
PubMed2026

Plant cis-regulatory grammar: Decoding the multidimensional code of transcriptional regulation for programmable crop engineering.

Cis-regulatory elements (CREs) orchestrate the spatiotemporal precision of gene expression that underlies plant development, adaptation, and domestication. Decoding the cis-regulatory grammar of plant genomes remains a central challenge in modern biology, with profound implications for programmable crop engineering. Here, recent conceptual and technological advances are synthesized to reshape our understanding of plant CREs. This review first argues that CRE function is not only an intrinsic property of DNA sequence alone but also emerges from a multidimensional context, including chromatin accessibility, histone modifications, three-dimensional genome topology, and cell type-specific regulatory landscapes. Furthermore, the convergence of single-cell epigenomics, high-throughput functional assays, and CRISPR-based dissection has begun to unravel this contextual grammar, revealing the computational principles governing transcriptional regulation. Critically, we propose that artificial intelligence (AI) platforms are catalyzing an ongoing transition from descriptive discovery to predictive engineering, wherein these platforms outperform natural evolution in designing synthetic CREs. Finally, a roadmap is outlined toward a plant regulatory grammar foundation model, which will enable truly predictive engineering of gene expression when fine-tuned for specific tasks. Collectively, the integration of single-cell resolution maps, precise genome editing, AI-driven design, and regulatory-compliant delivery systems promises to transform our ability to reprogram plant gene regulation for next-generation agriculture, bridging the gap between foundational regulatory biology and tangible crop improvement.

artificial intelligence↗
PubMed2026

Polycomb protein ZmEMF1a restricts endosperm proliferation and directs differentiation via stage-specific H2Aub1 and H3K27me3 landscapes in maize.

Polycomb group (PcG) proteins serve as pivotal epigenetic repressors that govern the transcriptional programs underlying cell growth and differentiation. However, their functional roles in maize endosperm remain largely unexplored. Here, we characterize the recessive maize small-kernel mutant sks1, which exhibits persistent endosperm cell hyperproliferation and compromised cell expansion during grain filling. Map-based cloning reveals that SKS1 encodes ZmEMF1a, a PcG protein that physically interacts with subunits of both PRC1 and PRC2. Integrated ChIP-seq and RNA-seq analyses were performed to investigate its epigenetic regulatory functions. ZmEMF1a orchestrates a stage-specific epigenetic regulatory program: it predominantly mediates H3K27me3 deposition at 6 d after pollination (DAP), while coordinately regulating the deposition of both H3K27me3 and H2Aub1 at 10 DAP. Loss of ZmEMF1a leads to ectopic hyperproliferation of differentiated endosperm tissues, specifically the basal endosperm transfer layer (BETL) and aleurone (AL), as well as elevated vitamin B content in the endosperm. Collectively, these findings establish ZmEMF1a as an epigenetic regulator that balances endosperm proliferation, cell fate specification, and nutrient accumulation through stage-specific histone modifications, thereby offering promising targets for enhancing maize yield and nutritional quality.

H2Aub1↗
PubMed2025

EucaMOD: a comprehensive multi-omics database for functional genomics research and molecular breeding of fast-growing eucalyptus trees.

Eucalyptus, one of the most widely planted plantation tree species globally, is primarily found in tropical and subtropical regions and contributes significantly to economic and social benefits. With advances in sequencing technologies, there is an increasing demand for the systematic analysis of multi-omics data among Eucalyptus species to enhance genetic breeding efforts. Although several early genomic databases have been established for eucalyptus, they have not been updated in a timely manner and lack recent multi-omics data, rendering them insufficient for current research needs. To address this gap, we developed the eucalyptus multi-omics database (EucaMOD, http://eucalyptusggd.net/eucamod), a comprehensive resource for cross-omics studies. In this study, we functionally annotated 45 eucalyptus genomes and structurally annotated 15, conducting comparative genomics and pan-proteomics analyses across all genomes. Additionally, we analyzed eucalyptus transcriptome, epigenome, and variome data through standardized workflows, enabling the in-depth mining and reanalysis of multi-omics datasets. EucaMOD is the most comprehensive multi-omics database for eucalyptus to date and includes data from 45 genomes (39 species), 870 mRNA-seq samples, 17 miRNA-seq samples, 52 epigenomic datasets (histone modifications and transcription factor binding), and genetic variation data from 1219 samples. To support functional genomics and molecular breeding research, the database is organized into the following 11 modules: Home, Species, Genomics, Comparative genomics, Pan-proteomics, Transcriptomics, Epigenetics, Variomics, Tools, Download, and Help. EucaMOD also offers online analysis tools for data mining, providing free public services to aid eucalyptus gene function and genetic engineering studies.

Eucalyptus↗
PubMed2004

Dynamic control of nuclear receptor transcription.

This Perspective highlights experiments that probe the complexity and regulation underlying cyclical association of nuclear receptor transcriptional complexes with DNA. Using advanced in vivo and in vitro techniques, these studies emphasize the importance of chromatin remodeling and histone modification in defining the timing and nature of the cycles. In addition, they reveal the multiplicity of receptor-coregulator complexes that reside on a single promoter. These conceptual and technical achievements integrate kinetic and combinatorial regulation into a new dynamic model of nuclear receptor-mediated transcription.

Cell Nucleus↗
PubMed2006

Cooperative activity of BRG1 and Z-DNA formation in chromatin remodeling.

The mammalian genome contains tens of thousands of CG and TG repeat sequences that have high potential to form the nonclassical left-handed double-helical Z-DNA structure. Previously we showed that activation of the colony-stimulating factor 1 (CSF1) gene by the chromatin remodeling enzyme, BRG1, results in formation of Z-DNA at the TG repeat sequence located within the promoter. In this report, we show that the TG repeats are assembled in a positioned nucleosome in the silent CSF1 promoter and that activation by BRG1 disrupts this nucleosome and results in Z-DNA formation. Active transcription is not required for the formation of Z-DNA but does result in an expanded region of Z-DNA. Formation of sequences by both BRG1 and the Z-DNA is required for effective chromatin remodeling of the CSF1 promoter. We propose the Z-DNA formation induced by BRG1 promotes a transition from a transient and partial remodeling to a more extensive disruption of the canonical nucleosomal structure. The data presented in this report establish that Z-DNA formation is an important mechanism in modulating chromatin structure, in similarity to the activities of ATP-dependent remodelers and posttranslational histone modifications.

Cells, Cultured↗