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PubMed2026

Fetal signatures in the 3D genome of iPSC-derived neurons and their implications for disease modeling.

Induced pluripotent stem cells (iPSCs) have revolutionized neuroscience, providing an approach to generate patient-specific neurons for modeling of neurological diseases. However, it remains unclear how closely iPSC-derived neurons replicate the chromatin architecture of authentic brain neurons. Here, we uniformly processed newly generated Hi-C data from iPSC-derived neurons and neurons isolated from the human postmortem brain, together with previously published data sets comprising 228 human and 89 mouse Hi-C and snm3C-seq samples from different cell subtypes. These data were merged into 96 high-coverage contact maps used to examine chromatin features ranging from chromatin compartments and topologically associating domains (TADs) to chromatin loops, Polycomb-mediated contacts, and frequently interacting regions (FIREs). We find that iPSC-derived neurons largely retain the chromatin state of undifferentiated cells and resemble fetal rather than mature neurons. iPSC-derived neurons exhibit unusually strong compartmentalization, an enrichment of developmental genes at TAD borders, and a marked reduction of long-range repressive Polycomb-mediated contacts that typically silence early fetal programs. Although immature, iPSC-derived neurons offer advantages for modeling interactions between disease-associated SNPs and target genes, as many psychiatric disorders have neurodevelopmental origins. Integrating iPSC-derived and postmortem neuronal data sets therefore provides complementary insights into the chromatin landscape underlying disease-associated interactions. Our study offers a valuable Hi-C resource for the community and provides a detailed comparison of chromatin architecture throughout neuronal maturation, underscoring its importance for validating neuronal models and providing a robust framework for future studies.

Journal Article↗
PubMed2026

Cultivar-dependent regulation of cytokinin biosynthesis in wheat: developmental expression of TaIPT genes and hormonal crosstalk during reproductive development.

BACKGROUND: Cytokinins are key regulators of plant growth, reproductive development, and yield formation. In cereals, cytokinin biosynthesis is catalyzed by isopentenyltransferase (IPT) enzymes, yet the genomic organization and developmental regulation of IPT genes in polyploid wheat remain incompletely understood, especially at the cultivar level. RESULTS: Here, we present an integrated genomic, transcriptional, and hormonal analysis of the TaIPT gene family during vegetative and reproductive development in two wheat cultivars, awnless Kontesa and awned Ostka. Genome-wide analysis identified nine core TaIPT genes represented by 25 homoeologs distributed across the A, B, and D subgenomes, for which a unified nomenclature was established. Phylogenetic analysis resolved TaIPTs into conserved evolutionary clades corresponding to ATP/ADP-dependent and tRNA-dependent IPT groups. Expression profiling revealed distinct spatial and temporal patterns of TaIPT transcription across roots, leaves, inflorescences, and developing spikes. Several TaIPT genes showed enhanced expression during early reproductive stages, coinciding with dynamic changes in cytokinin concentrations. Comparative analyses revealed cultivar-specific expression and co-variation patterns, with Kontesa displaying more compartmentalized TaIPT expression and Ostka showing coordinated activation of multiple TaIPT genes during early grain development. Hormone profiling further indicated stage-dependent associations between TaIPT expression, cytokinin metabolism, and the balance between cytokinins and abscisic acid. These relationships are interpreted as correlative and provide a framework for future functional testing rather than direct evidence of causality. CONCLUSIONS: Together, these results provide a cultivar-focused framework for understanding the organization and regulation of cytokinin biosynthesis genes in wheat. The data highlight cultivar-dependent TaIPT expression patterns and their association with cytokinin dynamics during reproductive development, while also identifying the need for homoeolog-specific and functional validation. This study establishes a foundation for future research on cytokinin-mediated regulation of wheat growth and grain development.

Triticum↗
PubMed2019

Replication timing networks reveal a link between transcription regulatory circuits and replication timing control.

DNA replication occurs in a defined temporal order known as the replication timing (RT) program and is regulated during development, coordinated with 3D genome organization and transcriptional activity. However, transcription and RT are not sufficiently coordinated to predict each other, suggesting an indirect relationship. Here, we exploit genome-wide RT profiles from 15 human cell types and intermediate differentiation stages derived from human embryonic stem cells to construct different types of RT regulatory networks. First, we constructed networks based on the coordinated RT changes during cell fate commitment to create highly complex RT networks composed of thousands of interactions that form specific functional subnetwork communities. We also constructed directional regulatory networks based on the order of RT changes within cell lineages, and identified master regulators of differentiation pathways. Finally, we explored relationships between RT networks and transcriptional regulatory networks (TRNs) by combining them into more complex circuitries of composite and bipartite networks. Results identified novel trans interactions linking transcription factors that are core to the regulatory circuitry of each cell type to RT changes occurring in those cell types. These core transcription factors were found to bind cooperatively to sites in the affected replication domains, providing provocative evidence that they constitute biologically significant directional interactions. Our findings suggest a regulatory link between the establishment of cell-type-specific TRNs and RT control during lineage specification.

Cell Differentiation↗
PubMed2019

Distinct types of short open reading frames are translated in plant cells.

Genomes contain millions of short (<100 codons) open reading frames (sORFs), which are usually dismissed during gene annotation. Nevertheless, peptides encoded by such sORFs can play important biological roles, and their impact on cellular processes has long been underestimated. Here, we analyzed approximately 70,000 transcribed sORFs in the model plant Physcomitrella patens (moss). Several distinct classes of sORFs that differ in terms of their position on transcripts and the level of evolutionary conservation are present in the moss genome. Over 5000 sORFs were conserved in at least one of 10 plant species examined. Mass spectrometry analysis of proteomic and peptidomic data sets suggested that tens of sORFs located on distinct parts of mRNAs and long noncoding RNAs (lncRNAs) are translated, including conserved sORFs. Translational analysis of the sORFs and main ORFs at a single locus suggested the existence of genes that code for multiple proteins and peptides with tissue-specific expression. Functional analysis of four lncRNA-encoded peptides showed that sORFs-encoded peptides are involved in regulation of growth and differentiation in moss. Knocking out lncRNA-encoded peptides resulted in a decrease of moss growth. In contrast, the overexpression of these peptides resulted in a diverse range of phenotypic effects. Our results thus open new avenues for discovering novel, biologically active peptides in the plant kingdom.

Bryopsida↗
PubMed2005

AnoEST: toward A. gambiae functional genomics.

Here, we present an analysis of 215,634 EST and cDNA sequences of a major vector of human malaria Anopheles gambiae structured into the AnoEST database. The expressed sequences are grouped into clusters using genomic sequence as template and associated with inferred functional annotation, including the following: corresponding Ensembl gene prediction, putative orthologous genes in other species, homology to known proteins, protein domains, associated Gene Ontology terms, and corresponding classification into broad GO-slim functional groups. AnoEST is a vital resource for interpretation of expression profiles derived using recently developed A. gambiae cDNA microarrays. Using these cDNA microarrays, we have experimentally confirmed the expression of 7961 clusters during mosquito development. Of these, 3100 are not associated with currently predicted genes. Moreover, we found that clusters with confirmed expression are nonbiased with respect to the current gene annotation or homology to known proteins. Consequently, we expect that many as yet unconfirmed clusters are likely to be actual A. gambiae genes. [AnoEST is publicly available at http://komar.embl.de, and is also accessible as a Distributed Annotation Service (DAS).].

Animals↗
PubMed2026

Microrna Expression in Aurelia aurita Metamorphosis.

INTRODUCTION: In animal taxa and jellyfish, the same genome encodes for the different phenotypes that characterize life stages that follow each other during ontogeny. This situation underscores the existence of profound regulation of genomic information at the epigenetic level. MicroRNAs are fundamental epigenetic regulators. The aim of this study is to evaluate the role of microRNA regulation during jellyfish metamorphosis and to explore the existence of evolutionarily conserved microRNAs. METHODS: Specimens belonging to the 4-metamorphosis stages of A. aurita (polyps, ephyra, young, and adult jellyfish) were bred and collected. The expression of 2,549 miRNAs for each stage was tested using microarray technology. The comparison of microRNA expression for each phase was performed using line plot analysis and Principal Component Analysis of variance (PCA), while the identification of microRNA clusters was performed via volcano plot analysis. RESULTS: A remarkable number of A. aurita miRNAs specifically hybridize with a human miRNA library. Each metamorphosis stage is characterized by a different level of expression of miRNAs: 1) Polyp vs. Ephyra stage: 128 upregulated, 2 downregulated; 2) Ephyra vs. Young stage: 2 upregulated, 135 downregulated; 3) Young vs. Adult stage: 69 upregulated, 6 downregulated. Specific functions inferred from known activities of corresponding miRNAs in higher animals (PubMed database) appear to be coherent with the correlated experimental model. DISCUSSION: Present results reveal that microRNAs with human homologs undergo specific expression changes throughout Aurelia aurita metamorphosis. This observation reinforces the hypothesis of a shared evolutionary origin of certain miRNA families between Cnidaria and Bilateria. The dynamic and stage-specific regulation pattern observed suggests that miRNAs play a key role in orchestrating the complex transitions involved in jellyfish development. These findings point to a broader conservation of epigenetic mechanisms, such as miRNA-mediated gene silencing, which may have emerged early in metazoan evolution and contributed to the regulation of cell differentiation and phenotype modulation. CONCLUSION: The present study highlights the importance of Aurelia aurita as a model for investigating miRNA-driven epigenetic regulation in non-bilaterian animals. The identification of human-homologous miRNAs provides novel insights into the evolutionary stability of the epigenetic machinery and suggests conserved regulatory functions across distant taxa. Although limited by the use of a human-based microarray platform, the data presented here lay a solid foundation for future studies employing sequencing and functional assays to further explore the role of miRNAs in cnidarian development and evolution.

Animals↗
PubMed2026

Developmental analysis of the cone photoreceptor-less little skate retina reveals distinct Onecut1 isoforms.

The retinal development of elasmobranchs, the subclass comprising sharks, skates, and rays, remains poorly understood. This group is diverse in retinal phenotype, with many sharks and rays possessing rods together with one or more cone types. In contrast, the little skate (Leucoraja erinacea) has only a single rod photoreceptor type, which has been reported to exhibit some physiological and anatomical properties associated with cones. To investigate how this unusual photoreceptor system develops, we first identified an embryonic stage of early photoreceptor formation based on otx2 expression. We then developed a retinal electroporation approach to test whether a onecut1-dependent cone-associated reporter could be activated in the embryonic skate retina. Activation of this reporter was not detected, indicating that the corresponding enhancer is not robustly active under the conditions tested. To assess developmental changes in gene expression, we generated bulk RNA-seq datasets from embryonic, hatchling, and adult retinas. These analyses showed strong embryonic expression of onecut1, increasing expression of rod-associated genes through development, and pseudogenization or loss of multiple cone-enriched genes. We further identified a developmentally regulated onecut1 splice isoform containing an additional 48 amino acid sequence between the CUT and homeodomain DNA-binding domains. This spacer-containing isoform, termed LSOC1X2, was most abundant in the embryonic retina. To test whether LSOC1X2 retained regulatory activity, we assayed it in a mouse retinal reporter system. Both skate Onecut1 isoforms activated the ThrbCRM1 reporter in this heterologous context. Together, these findings identify a novel, developmentally regulated retinal onecut1 isoform in the little skate and establish it as a candidate regulator for future studies of photoreceptor development in this species and its elasmobranch relatives.

Animals↗
PubMed1976

Transcriptional control of T4 coliphage-specific genes 30, 42, 43, rIIA, rIIB, and e.

Escherichia coli B/r (suo) was infected, at 30 degrees C, with T4Dam+, T4DamB24-amN82 (I-, 44-, DNA-negative phenotype), and T4DamN134amBL292 (33-, 55-, maturation-defective phenotype). A genetic ('transformation') assay was used to monitor transcription of genes 30 (polynucleotide ligase), 42 (deoxycytidylate hydroxymethylase), 43 (DNA polymerase), rIIA, rIIB, and e (endolysin). The principal results are: (I) All of the genes studied were transcribed exlusively from the so-called l-strand of phage DNA. (2) DNA synthesis and the maturation-defective proteins were required to turn-off transcription of genes 42, rIIA, tIIB, and 43. Experiments performed with chloramphenicol suggested that all phage-specific proteins required to turn-off transcription of these genes were not present until 6 to 8 min post infection (p.i.). (3) During a normal developmental programme, gene 30 was transcribed throughout the eclipse. DNA-negative and maturation-defective conditions had no obvious effect on transcription of this gene. (4) During a normal lytic event, two discrete waves of gene e transcription were observed. The late wave was dependent upon DNA-synthesis and presence of functional maturation-defective proteins. The early wave was unaffected by DNA-negative or maturation-defective conditions. Experiments with chloramphenicol indicated that, if any virus-specific proteins are involved with regulation of early e transcription, such proteins are present by 3 min p.i. The data are interpreted to mean that early gene transcription is regulated by a minimum of two mechanisms. One of these mechanisms is fully operational by the 3rd min and, among the genes studied, controlled early e transcription. A second mechanism becomes operational between 6 and 8 min p.i. and controls transcription of genes 42, 43, rIIA, and rIIB.

Animals↗
PubMed2021

Functional impact of cancer-associated cohesin variants on gene expression and cellular identity.

Cohesin is a ring-shaped protein complex that controls dynamic chromosome structure. Cohesin activity is important for a variety of biological processes, including formation of DNA loops that regulate gene expression. The precise mechanisms by which cohesin shapes local chromosome structure and gene expression are not fully understood. Recurrent mutations in cohesin complex members have been reported in various cancers, though it is not clear whether many cohesin sequence variants have phenotypes and contribute to disease. Here, we utilized CRISPR/Cas9 genome editing to introduce a variety of cohesin sequence variants into murine embryonic stem cells and investigate their molecular and cellular consequences. Some of the cohesin variants tested caused changes to transcription, including altered expression of gene encoding lineage-specifying developmental regulators. Altered gene expression was also observed at insulated neighborhoods, where cohesin-mediated DNA loops constrain potential interactions between genes and enhancers. Furthermore, some cohesin variants altered the proliferation rate and differentiation potential of murine embryonic stem cells. This study provides a functional comparison of cohesin variants found in cancer within an isogenic system, revealing the relative roles of various cohesin perturbations on gene expression and maintenance of cellular identity.

Animals↗
PubMed2026

Developmental genetic determinants of the human cerebrospinal fluid-ventricular system.

Primary enlargement of the cerebrospinal fluid (CSF)-filled brain ventricles, known as congenital cerebral ventriculomegaly (CCV), is a hallmark of congenital hydrocephalus. CCV is also enigmatically but frequently associated with autism and other neurodevelopmental disorders. To gain insight into the developmental genetic regulation of the human CSF-ventricular system, we conducted an integrated, multiomic study of about 2700 trio-based exomes from patients with primary CCV. We found that about 25% of cases were associated with rare, damaging de novo variants in mutation-intolerant genes, many of which are linked to other dominant Mendelian disorders. Thirty-five exome-wide significant CCV genes and dozens of other high-confidence CCV genes converged on pathways involved in ATP-dependent Brahma-related gene 1/Brahma-associated factor chromatin remodeling, histone H3 lysine 4 methylation, and phosphoinositide 3-kinase signaling. Knockout of selected CCV genes in mouse models supported that de novo variants in CCV genes caused ventriculomegaly by impairing both CSF dynamics and cortical cytoarchitecture through dysregulation of neuroprogenitor cell growth and maturation in the ventricular and subventricular zones. These findings indicated that genetic and epigenetic programs coordinate the "hand-in-glove" development of the CSF-ventricular system with that of the cerebral cortex and establish a genetic connection between CCV and neurodevelopmental disorders, potentially explaining why some patients with hydrocephalus continue to exhibit CCV and neurodevelopmental disorders despite CSF shunting. We suggest that combined brain imaging and whole-exome sequencing could enable early detection of, and intervention for, autism and other neurodevelopmental disorders.

Humans↗
PubMed1975

Albinism and auditory function in the laboratory mouse. I. Effects of single-gene substitutions on auditory physiology, audiogenic seizures, and developmental processes.

The effects of single-gene albino (c/c) mutations on auditory behavior and physiology were examined in congenic C57BL/6J mice. At 16 days of age, the c gene was additively associated with both reduced auditory functioning and lower body weight: 16-day-old c/c mice had higher auditory evoked potential (AEP) thresholds than +/c mice, which, in turn, had higher thresholds than +/+ mice; +/c mice were also intermediate with regard to body weight. Since these differences had nearly disappeared by 21 days of age, it was concluded that the c genes worked in an additive fashion to delay development during the period previously (Henry, 1967) found critical for inducing susceptibility to audiogenic seizures. At 16 days of age, albino mice (c/c) displayed susceptibility to audiogenic seizures, but nonalbino genotypes (+/c and +/+) were immune to the convulsive effects of sound. This behavior appeared to be a recessive trait at this age. But 5 days later, the behavioral phenotype exhibited incomplete dominance, with the +/c genotype displaying audiogenic seizures intermediate to those seen in the susceptible c/c and the nonsusceptible +/+ genotypes. These behaviors were compared to the thresholds and peak-to-peak amplitudes of the AEP, as seen in the input-output functions. It is suggested that differential development of the auditory systems in these genotypes is causally related to susceptibility to audiogenic seizures.

Acoustic Stimulation↗
PubMed1978

Developmental restrictions on hormone modulated gene transcription. II. Hormone induced interactions of RNA polymerase with chromatin.

Chromatin-bound and soluble RNA polymerase subspecies have been isolated and fractionated by isoelectric focusing at various times (0, 6, 12 and 18 h) following auxin treatment of 4 day (responsive) and 8 day (unresponsive) soybean hypocotyls. Young 4 day seedlings displayed two well defined phases of auxin induced gene transcription. Phase I (6 h) evidenced the selective dissociation of many RNA polymerase subspecies from the chromatin complex which was accompanied by the retention of three class II enzymes. Phase II occurred after 12 h of treatment when the dissociated enzymes including some species which were soluble in the 0 h controls became re-associated with chromatin. These induced RNA polymerases may be responsible for the synthesis of auxin induced RNAs. In contrast, the unresponsive 8 day hypocotyl did not display two phases of auxin induction. Phase one, the dissociation of the chromatin bound enzymes, occurred at 12 h (compared to 6 h for the 4 day seedling) and was not followed by the later translocation of any soluble enzymes towards the chromatin complex. The results support earlier findings suggesting that the developmental "phasing out" of RNA polymerase subspecies limits the hormone induced growth response of this tissue and thus is regarded as an off switch for the transcription of such hormone controlled gene sequences.

2,4-Dichlorophenoxyacetic Acid↗
PubMed2026

A framework to infer de novo exonic variants when parental genotypes are missing enhances association studies of autism.

MOTIVATION: Gene-damaging mutations are highly informative for studies seeking to discover genes underlying developmental disorders. Traditionally, these de novo variants are recognized by evaluating high-quality DNA sequence from affected offspring and parents. However, when parental sequence is unavailable, methods are required to infer de novo status and use this inference for association studies. RESULTS: We use data from autism spectrum disorder to illustrate and evaluate methods. Separating de novo from rare inherited variants is challenging because the latter are far more common. Using a classifier for unbalanced data and variants of known inheritance class, we build an inheritance model and then a de novo score for variants when parental data are missing. Next, we propose a new Random Draw (RD) model to use this score for gene discovery. Built into an existing inferential framework, RD produces a more powerful gene-based association test and controls the false discovery rate. AVAILABILITY AND IMPLEMENTATION: Codes are available at Github (https://github.com/HaeunM/TADA-RD) and Zenodo (DOI: https://doi.org/10.5281/zenodo.18531769).

Humans↗
PubMed2026

Insights into the regulatory roles of LIKE-HETEROCHROMATIN PROTEIN 1 and its targeting to different nuclear compartments modulated by NLS and the conserved domains in the moss Physcomitrium patens.

LIKE-HETEROCHROMATIN PROTEIN 1 (LHP1) is a polycomb group protein that exists in shared multiprotein complexes that harbor core PRC1 and PRC2 proteins. We previously characterized LHP1 in the moss Physcomitrium patens and showed that its function is closely linked with regulation of RNA metabolic processes and the protein is distributed in the nucleoplasm, subnuclear foci, and the nucleolus. To gain mechanistic insight into PpLHP1-mediated gene regulation, in the present study genome-wide changes in transcript profiles of genes affected by loss-of-PpLHP1 function were studied using pplhp1 mutants. RNA-seq analysis reveals a key role for PpLHP1 in regulating energy metabolic processes, ribosome-related pathways, stress signaling/responsive pathways, DNA transcription, etc. ChIP using H3K27me3 coupled with qRT-PCR shows that PpLHP1 suppresses transcription at 5S rRNA promoters and the untimely activation of genes regulating developmental transition by PRC2-dependent and independent mechanisms. To study how PpLHP1 finds its targets in different nuclear compartments and the roles of the multiple NLSs and the conserved domains in guiding the protein, FRAP and deletion studies were performed. These show that PpLHP1 is a mobile protein that diffuses freely in the nucleoplasmic space showing different retention times in the nucleolus, nucleoplasm, and the subnuclear foci indicating its differential affinity for targets at these sites. Expression of PpLHP1 fragments in protonema cells and its subsequent visualization under confocal microscope shows that localization of PpLHP1 to different subnuclear compartments is guided by the monopartite NLS2, CD, and CSD that also play a key role in promoting subnuclear foci formation in the nucleoplasm.

Bryopsida↗
PubMed2026

Cryo-EM structure, enzymatic activity and genome targeting of canonical PRC1.

Canonical Polycomb repressive complex 1 (cPRC1) preserves cell fate decisions by repressing aberrant transcription of developmental regulator genes. We report the cryo-electron microscopy structure of the human cPRC1 holocomplex assembled from RING1B, BMI1, PHC2 and CBX7 bound to an H3K27me3-modified mononucleosome together with the ubiquitin-conjugating enzyme UBCH5C. cPRC1 adopts a compact, highly integrated architecture in which the subunits RING1B, BMI1 and PHC2 form an extended interface that positions UBCH5C on the nucleosome to enable efficient monoubiquitination of histone H2A at K119. This organization is conserved in Drosophila, where mutational analyses identify the PHC2 ortholog Polyhomeotic (Ph) as a central scaffold and targeting factor. The Ph HD domain is required for complex assembly, whereas the Ph SAM domain is dispensable for assembly but essential for cPRC1 recruitment to Polycomb target genes and productive H2A monoubiquitination at these loci.

Journal Article↗
PubMed1979

Developmental studies of the lethal gene Bld in the mouse. I. Post-implantation development of the lethal homozygote.

In matings of Bld/+ x Bld/+ mice a characteristic type of abnormal embryo is found on days 6 and 7 after impregnation which dies at 8 days and accounts for about 25% of all living embryos. These embryos are regarded as the fethal Bld/Bld homozygotes. Before 6 days the embryos appear slightly retarded. Entodermal cells invade the yolk sac and the trophectoderm does not fuse to the uterine decidua. Late on day 6 the yolk sac is filled with a cap of unorganized cells of entodermal origin, surrounded by both a thick membrane of non-living material, corresponding to Reichert's membrane, and external to this a continuous layer of trophectoderm: there is still almost no contact with uterine tissue. At 7 days 10 h amniotic folds are formed. Mesoderm appears occasionally but is not always present; when it appears it does not grow out from its place of origin. Entodermal cells, particularly in the proximal part of the extra-embryonic region, become polyploid. At the same time, the trophectoderm makes contact with the uterine decidua and gives rise to primary giant cells. Twelve hours later, the embryonic cells begin to degenerate, first in the region of the amniotic fold and the mesoderm. The embryo dies shortly afterwards. It is suggested that the primary target tissues affected by the Bld/Bld constitution are trophectoderm and entoderm. Many but not all of the abnormal features appearing later can by ascribed to insufficient nutrition of the embryo, due to failure of attachment of the trophectoderm and the filling of the yolk sac with entodermal cells.

Animals↗