Developmental Gene Expression Research Articles

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 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 8,000 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.

Dynamic changes in insulin-like growth factor binding protein expression occur between embryonic and early post-hatch development in broiler chickens

Somatotropic gene expression has been altered by genetic selection, and developmental changes in insulin-like growth factor (IGF) and IGF binding protein (IGFBP) expression may contribute to rapid growth and muscle accretion in commercial broilers. The objective of this study was to evaluate changes in somatotropic axis activity between embryonic day (e) 12 and post-hatch day (d) 21. Liver and breast muscle (pectoralis major) were collected to measure gene expression, and blood was collected post-hatch to measure circulating IGFs. Liver IGF1 rose rapidly post-hatch and, in muscle, IGF1 exhibited a dynamic expression pattern. Levels decreased from e14 to e20, returned to e14 levels at d3, decreased again at d10, and stayed low thereafter. In both tissues, mRNA levels of several IGFBPs changed between embryogenesis and post-hatch. Liver IGFBP2 increased between e12 and e20, returned to e12 levels on d1, and remained low. Conversely, liver IGFBP4 expression was greater post-hatch than during embryogenesis. Expression of select IGFBPs was depressed in liver during the peri-hatch period. Liver IGFBP1, IGFBP3, IGFBP5, and IGFBP7 mRNA levels all decreased around this time and returned to embryonic levels by d3. In breast muscle, expression of both IGFBP2 and IGFBP4 was reduced after hatch. Circulating insulin-like growth factor IGF1 and IGF2 levels did not change between hatch and d21. These data suggest that post-hatch IGF effects are likely modulated by target tissue IGFR1 and IGFBP expression rather than changes in circulating hormone levels, with promotion or restriction of IGF-receptor binding regulating growth. Downregulation of several IGFBPs synthesized in the liver may facilitate the metabolic transition from utilizing yolk lipids to dietary carbohydrates. Several IGFBPs produced in breast muscle appear to have growth-promotive effects during embryogenesis but restrict growth of this tissue after hatch, as their post-hatch downregulation could facilitate local IGF signaling. These developmental gene expression patterns suggest that somatotropic hormonal signaling regulating growth and muscle accretion might be controlled through differential actions of IGFBPs and provide a basis for future functional studies.

A spatiotemporally resolved atlas of mRNA decay in the C. elegans embryo reveals differential regulation of mRNA stability across stages and cell types.

During embryonic development, cells undergo dynamic changes in gene expression that are required for appropriate cell fate specification. Although both transcription and mRNA degradation contribute to gene expression dynamics, patterns of mRNA decay are less well understood. Here, we directly measure spatiotemporally resolved mRNA decay rates transcriptome-wide throughout C. elegans embryogenesis by transcription inhibition followed by bulk and single-cell RNA sequencing. This allows us to calculate mRNA half-lives within specific cell types and developmental stages, and identify differentially regulated mRNA decay throughout embryonic development. We identify transcript features that are correlated with mRNA stability and find that mRNA decay rates are associated with distinct peaks in gene expression over time. Moreover, we provide evidence that, on average, mRNA is more stable in the germline than in the soma and in later embryonic stages than in earlier stages. This work suggests that differential mRNA decay across cell states and time helps to shape developmental gene expression, and it provides a valuable resource for studies of mRNA turnover regulatory mechanisms.

Evolution of the regulation of developmental gene expression in blind Mexican cavefish.

Developmental evolution and diversification of morphology can arise through changes in the regulation of gene expression or protein-coding sequence. To unravel mechanisms underlying early developmental evolution in cavefish of the species Astyanax mexicanus, we compared transcriptomes of surface-dwelling and blind cave-adapted morphs at the end of gastrulation. Twenty percent of the transcriptome was differentially expressed. Allelic expression ratios in cave X surface hybrids showed that cis-regulatory changes are the quasi-exclusive contributors to inter-morph variations in gene expression. Among a list of 108 genes with change at the cis-regulatory level, we explored the control of expression of rx3, which is a master eye gene. We discovered that cellular rx3 levels are cis-regulated in a cell-autonomous manner, whereas rx3 domain size depends on non-autonomous Wnt and Bmp signalling. These results highlight how uncoupled mechanisms and regulatory modules control developmental gene expression and shape morphological changes. Finally, a transcriptome-wide search for fixed coding mutations and differential exon use suggested that variations in coding sequence have a minor contribution. Thus, during early embryogenesis, changes in gene expression regulation are the main drivers of cavefish developmental evolution.

Mesomelia-synostoses syndrome: contiguous deletion syndrome, SULF1 haploinsufficiency or enhancer adoption?

BackgroundMesomelia-Synostoses Syndrome (MSS)(OMIM 600,383) is a rare autosomal dominant disorder characterized by mesomelic limb shortening, acral synostoses and multiple congenital malformations which is described as a contiguous deletion syndrome involving the two genes SULF1 and SLCO5A1. The study of apparently balanced chromosomal rearrangements (BCRs) is a cytogenetic strategy used to identify candidate genes associated with Mendelian diseases or abnormal phenotypes. With the improved development of genomic technologies, new methods refine this search, allowing better delineation of breakpoints as well as more accurate genotype-phenotype correlation.Case presentationWe present a boy with a global development deficit, delayed speech development and an ASD (Asperger) family history, with an apparently balanced “de novo” reciprocal translocation [t(1;8)(p32.2;q13)dn]. The cytogenetic molecular study identified a likely pathogenic deletion of 21 kb in the 15q12 region, while mate pair sequencing identified gene-truncations at both the 1p32.2 and 8q13 translocation breakpoints.ConclusionsThe identification of a pathogenic alteration on 15q12 involving GABRA5 was likely the main cause of the ASD-phenotype. Importantly, the chr8 translocation breakpoint truncating SLCO5A1 exclude SLCO5A1 as a candidate for MSS, leaving SULF1 as the primary candidate. However, the deletions observed in MSS remove a topological associated domain (TAD) boundary separating SULF1 and SLCO5A1. Hence, Mesomelia-Synostoses syndrome is either caused by haploinsufficiency of SULF1 or ectopic enhancer effects where skeletal/chrondrogenic SULF1 enhancers drive excopic expression of developmental genes in adjacent TADs including PRDM14, NCOA2 and/or EYA1.

Regeneration recapitulates many embryonic processes, including reuse of developmental regulatory regions.

The wide distribution of regenerative capacity across the animal tree of life raises the question of how regeneration has evolved in distantly-related animals. Given that whole-body regeneration shares the same end-point - formation of a functional body plan - as embryonic development, it has been proposed that regeneration likely recapitulates developmental processes to some extent. Therefore, understanding how developmental processes are reactivated during regeneration is important for uncovering the evolutionary history of regeneration. Comparative transcriptomic studies in some species have revealed shared gene expression between development and regeneration, but it is not known whether these shared expression profiles correspond to shared functions, and which mechanisms activate expression of developmental genes during regeneration. We sought to address these questions using the acoel Hofstenia miamia , which is amenable to studies of both embryonic development and whole-body regeneration. By examining functionally validated regeneration processes during development at single-cell resolution, we found that whereas patterning and cellular differentiation are largely similar, wound response programs have distinct dynamics between development and regeneration. Chromatin accessibility analyses revealed that regardless of playing concordant or divergent roles during regeneration and development, genes expressed in both processes are frequently controlled by the same regulatory regions, potentially via utilization of distinct transcription factor binding sites. This study extends the known correspondence of development and regeneration from broad transcriptomic similarity to include patterning and differentiation processes. Further, our work provides a catalog of regulatory regions and binding sites that potentially regulate developmental genes during regeneration, fueling comparative studies of regeneration.

The activity of early-life gene regulatory elements is hijacked in aging through pervasive AP-1-linked chromatin opening

A mechanistic connection between aging and development is largely unexplored. Through profiling age-related chromatin and transcriptional changes across 22 murine cell types, analyzed alongside previous mouse and human organismal maturation datasets, we uncovered a transcription factor binding site (TFBS) signature common to both processes. Early-life candidate cis-regulatory elements (cCREs), progressively losing accessibility during maturation and aging, are enriched for cell-type identity TFBSs. Conversely, cCREs gaining accessibility throughout life have a lower abundance of cell identity TFBSs but elevated activator protein 1 (AP-1) levels. We implicate TF redistribution toward these AP-1 TFBS-rich cCREs, in synergy with mild downregulation of cell identity TFs, as driving early-life cCRE accessibility loss and altering developmental and metabolic gene expression. Such remodeling can be triggered by elevating AP-1 or depleting repressive H3K27me3. We propose that AP-1-linked chromatin opening drives organismal maturation by disrupting cell identity TFBS-rich cCREs, thereby reprogramming transcriptome and cell function, a mechanism hijacked in aging through ongoing chromatin opening.

Circulating plasma fibronectin affects tissue insulin sensitivity, adipocyte differentiation, and transcriptional landscape of adipose tissue in mice.

Plasma fibronectin (pFN) is a hepatocyte-derived circulating extracellular matrix protein that affects cell morphology, adipogenesis, and insulin signaling of adipocytes invitro. In this study, we show pFN accrual to adipose tissue and its contribution to tissue homeostasis in mice. Hepatocyte-specific conditional Fn1 knockout mice (Fn1-/-ALB) show a decrease in adipose tissue FN levels and enhanced insulin sensitivity of subcutaneous (inguinal), visceral (epididymal) adipose tissue on a normal diet. Diet-induced obesity model of the Fn1-/-ALB mouse showed normal weight gain and whole-body fat mass, and normal adipose tissue depot volumes and unaltered circulating leptin and adiponectin levels. However, Fn1-/-ALB adipose depots showed significant alterations in adipocyte size and gene expression profiles. The inguinal adipose tissue on a normal diet, which had alterations in fatty acid metabolism and thermogenesis suggesting browning. The presence of increased beige adipocyte markers Ucp1 and Prdm16 supported this. In the inguinal fat, the obesogenic diet resulted in downregulation of the browning markers and changes in gene expression reflecting development, morphogenesis, and mesenchymal stem cell maintenance. Epididymal adipose tissue showed alterations in developmental and stem cell gene expression on both diets. The data suggests a role for pFN in adipose tissue insulin sensitivity and cell profiles.

Intrapuparial stage aging and PMI estimation based on the developmental transcriptomes of forensically important Aldrichina grahami (Diptera: Calliphoridae) gene expression

BackgroundThe expression profiles of differentially expressed genes (DEGs) during pupal development have been demonstrated to be vital in age estimation of forensic entomological study. Here, using forensically important Aldrichina grahami (Diptera: Calliphoridae), we aimed to explore the potential of intrapuparial stage aging and postmortem interval (PMI) estimation based on characterization of successive developmental transcriptomes and gene expression patterns. MethodsWe collected A. grahami pupae at 11 successive intrapuparial stages at 20 °C and used the RNA-seq technique to build the transcriptome profiles of their intrapuparial stages. The DEGs were identified during the different intrapuparial stages using comparative transcriptome analysis. The selected marker DEGs were classified and clustered for intrapuparial stage aging and PMI estimation and then further verified for transcriptome data validation. Ultimately, we categorized the overall gene expression levels as the dependent variable and the age of intrapuparial A. grahami as the independent variable to conduct nonlinear regression analysis. ResultsWe redefined the intrapuparial stages of A. grahami into five key successive substages (I, II, III, IV, and V), based on the overall gene expression patterns during pupal development. We screened 99 specific time-dependent expressed genes (stage-specific DEGs) to determine the different intrapuparial stages based on comparison of the gene expression levels during the 11 developmental intrapuparial stages of A. grahami. We observed that 55 DEGs showed persistent upregulation during the development of intrapuparial A. grahami. We then selected four DEGs (act79b, act88f, up and ninac) which presented consistent upregulation using RT-qPCR (quantitative real-time PCR) analysis, along with consideration of the maximum fold changes during the pupal development. We conducted nonlinear regression analysis to simulate the calculations of the relationships between the expression levels of the four selected DEGs and the developmental time of intrapuparial A. grahami and constructed fitting curves. The curves demonstrated that act79b and ninac showed continuous relatively increasing levels. ConclusionsThis study redefined the intrapuparial stages of A. grahami based on expression profiles of developmental transcriptomes for the first time. The stage-specific DEGs and those with consistent tendencies of expression were found to have potential in age estimation of intrapuparial A. grahami and could be supplementary to a more accurate prediction of PMI.

MODL-12. REPURPOSING SSRI/SNRI TARGETING NEUROTRANSMITTER SIGNALING TO SENSITIZE DMG TO CDK9 INHIBITORS

Abstract BACKGROUND Diffuse Midline Glioma (DMG) comprise a subset of aggressive pediatric brain tumors with few effective therapies. Cyclin-dependent kinase 9 inhibitors (CDK9i) like zotiraciclib (ZTR) are in clinical trials for adult and pediatric glioma, but resistance frequently develops. In this study, we find that co-treatment with CDK9i and brain penetrant, FDA-approved drugs targeting neurotransmitter signaling alters DMG transcription and reduces DMG growth and tumorigenesis. METHODS We conducted drug screens to assess DMG response to a sub-threshold dose of ZTR combined with a library of ~220 bioactive and FDA-approved compounds. Combinatorial effects of CDK9i+SSRI/SNRI treatment were confirmed through in vitro dose curve studies and in orthotopic DMG xenograft models. We identified downstream targets of CDK9i+SSRI/SNRI treatment through phospho-proteomic profiling, RNAseq analysis, immunofluorescence staining, and Western blotting. RESULTS Our targeted drug screens identified SSRIs (selective serotonin reuptake inhibitors) and SNRIs (serotonin and norepinephrine reuptake inhibitors) that increase DMG sensitivity to a low dose of zotiraciclib (ZTR). Follow-up studies confirm that combinations of structurally distinct CDK9i (ZTR, AZD4573) and SSRI/SNRI (sertraline, duloxetine) synergistically reduce DMG growth in neurospheres, induce the apoptotic marker cleaved caspase 3, and reduce the expression of proliferation markers. Additional proteogenomic analyses define downstream targets of CDK9i+SSRI co-treatment, including differential phosphorylation of chromatin regulators and RNA Polymerase 2 (Pol2)-associated elongation factors and splicing machinery. Further RNAseq studies reveal robust transcriptional changes induced by CDK9i+SSRI treatment characterized by altered expression of developmental and synaptic signaling genes. Finally, pilot pre-clinical studies find that CDK9i+SSRI treatment reduces tumor growth and increases progression free survival in a DMG xenograft model. CONCLUSIONS We have identified synergistic CDK9i+SSRI drug combinations that can be applied to alter malignant gene regulation and reduce DMG growth in vitro and in xenografts. These studies provide a basis for a drug-repurposing strategy to combine SSRI/SNRI and CDK9 inhibitors for DMG treatment.

MDB-11. DOES THE INTRAOPERATIVE ASSESSMENT OF SITE OF ORIGIN OF MEDULLOBLASTOMA ALLOW FOR A TAILORING OF THE NEUROSURGICAL STRATEGY? DATA FROM A RETROSPECTIVE SINGLE-CENTER ASSESSMENT AND PROPOSAL OF A PROSPECTIVE MULTICENTER STUDY

Abstract BACKGROUND Developmental gene expression data from medulloblastoma (MB) suggest that WNT-MB originate from the region of the embryonic lower rhombic lip (LRL), whereas SHH-MB and non-WNT/non-SHH MB arise from cerebellar precursor matrix regions. This study aims to analyze detailed intraoperative data with regard to the site of origin (STO) and compare these findings with the hypothesized regions of origin associated with the molecular group. METHODS A review of the institutional database identified 58 out of 72 pediatric patients who were operated on a MB at our department between 1996 and 2020 that had a detailed operative report, surgical video as well as clinical and genetic classification data available for analysis. The STO was assessed based on intraoperative findings. RESULTS Using the intraoperatively defined STO, “correct” prediction of molecular groups was feasible in 20% of WNT-MB, 60% of SHH-MB and 71% of non-WNT/non-SHH MB. The positive predictive values of the neurosurgical inspection to detect the molecular group were 0.21 (95% CI 0.08–0.48) for WNT-MB, 0.86 (95% CI 0.49–0.97) for SHH-MB and 0.73 (95% CI 0.57–0.85) for non-WNT/non-SHH MB. CONCLUSION In our series of 58 well-documented cases, the intraoperative assessment of the STO could not reliably predict the molecular group. Thus, the current evidence does still not allow for intraoperative group-specific risk stratification that would enable tailoring the neurosurgical strategy to the prognostic and predictive profile of the patient. Prospective multicenter assessments are necessary to systematically evaluate the growth pattern and site of origin of medulloblastoma. Accordingly, a study protocol of an international cohort study will be presented.

A network comprising ELONGATED HYPOCOTYL5, microRNA397b, and auxin-associated factors regulates root hair growth in Arabidopsis.

ELONGATED HYPOCOTYL 5 (HY5) is a major light-associated transcription factor involved in plant growth and development. In Arabidopsis (Arabidopsis thaliana), the role of HY5 is very well-defined in regulating primary root growth and lateral root formation; however, information regarding its role in root hair development is still lacking, and little is known about the genetic pathways regulating this process. In this study, we investigated the role of HY5 and its associated components in root hair development. Detailed analysis of root hair phenotype in wild-type (WT) and light signaling mutants in light and dark conditions revealed the importance of light-dependent HY5-mediated root hair initiation. Altered auxin levels in the root apex of the hy5 mutant and interaction of HY5 with promoters of root hair developmental genes were responsible for differential expression of root hair developmental genes and phenotype in the hy5 mutant. The partial complementation of root hair in the hy5 mutant after external supplementation of auxin and regaining of root hair in PIN-FORMED 2 (pin2) and PIN-FORMED 2 (pin3) mutants after grafting suggested that the auxin-mediated root hair development pathway requires HY5. Furthermore, miR397b overexpression (miR397bOX) and CRISPR/Cas9-based mutants (miR397bCR) indicated miR397b targets genes encoding Reduced Residual Arabinose (RRA1/RRA2), which in turn regulate root hair growth. The regulation of the miR397b- (RRA1/RRA2) module by HY5 demonstrated its indirect role by targeting root hair cell wall genes. Together, this study demonstrated that HY5 controls root hair development by integrating auxin signalling and other miRNA-mediated pathways.

Temporal dynamics of faster neo-Z evolution in butterflies.

The faster-Z/X hypothesis predicts that sex-linked genes should diverge faster than autosomal genes. However, studies across different lineages have shown mixed support for this effect. So far, most analyses have focused on old and well-differentiated sex chromosomes, but less is known about the divergence of more recently acquired neo-sex chromosomes. In Lepidoptera (moths and butterflies), Z-autosome fusions are frequent, but the evolutionary dynamics of neo-Z chromosomes have not been explored in detail. Here, we analyzed the faster-Z effect in Leptidea sinapis, a butterfly with three Z chromosomes. We show that the neo-Z chromosomes have been acquired stepwise, resulting in strata of differentiation and masculinization. While all Z chromosomes showed evidence of the faster-Z effect, selection for genes on the youngest neo-Z chromosome (Z3) appears to have been hampered by a largely intact, homologous neo-W chromosome. However, the intermediately aged neo-Z chromosome (Z2), which lacks W gametologs, showed fewer evolutionary constraints, resulting in particularly fast evolution. Our results therefore support that neo-sex chromosomes can constitute temporary hot-spots of adaptation and divergence. The underlying dynamics are likely causally linked to shifts in selective constraints, evolution of gene expression, and degeneration of W-linked gametologs which gradually expose Z-linked genes to selection.

Chromatin profiling identifies putative dual roles for H3K27me3 in regulating transposons and cell type-specific genes in choanoflagellates.

Gene expression is tightly controlled during animal development to allow the formation of specialized cell types. Our understanding of how animals evolved this exquisite regulatory control remains elusive, but evidence suggests that changes in chromatin-based mechanisms may have contributed. To investigate this possibility, here we examine chromatin-based gene regulatory features in the closest relatives of animals, choanoflagellates. Using Salpingoeca rosetta as a model system, we examined chromatin accessibility and histone modifications at the genome scale and compared these features to gene expression. We first observed that accessible regions of chromatin are primarily associated with gene promoters and found no evidence of distal gene regulatory elements resembling the enhancers that animals deploy to regulate developmental gene expression. Remarkably, a histone modification deposited by polycomb repressive complex 2, histone H3 lysine 27 trimethylation (H3K27me3), appeared to function similarly in S. rosetta to its role in animals, because this modification decorated genes with cell type-specific expression. Additionally, H3K27me3 marked transposons, retaining what appears to be an ancestral role in regulating these elements. We further uncovered a putative new bivalent chromatin state at cell type-specific genes that consists of H3K27me3 and histone H3 lysine 4 mono-methylation (H3K4me1). Together, our discoveries support the scenario that gene-associated histone modification states that underpin development emerged before the evolution of animal multicellularity.

Using a hybrid neural network architecture for DNA sequence representation: A study on [formula omitted]-methylcytosine sites

N4-methylcytosine (4mC) is a modified form of cytosine found in DNA, contributing to epigenetic regulation. It exists in various genomes, including the Rosaceae family encompassing significant fruit crops like apples, cherries, and roses. Previous investigations have examined the distribution and functional implications of 4mC sites within the Rosaceae genome, focusing on their potential roles in gene expression regulation, environmental adaptation, and evolution. This research aims to improve the accuracy of predicting 4mC sites within the genome of Fragaria vesca, a Rosaceae plant species. Building upon the original 4mc-w2vec method, which combines word embedding processing and a convolutional neural network (CNN), we have incorporated additional feature encoding techniques and leveraged pre-trained natural language processing (NLP) models with different deep learning architectures including different forms of CNN, recurrent neural networks (RNN) and long short-term memory (LSTM). Our assessments have shown that the best model is derived from a CNN model using fastText encoding. This model demonstrates enhanced performance, achieving a sensitivity of 0.909, specificity of 0.77, and accuracy of 0.879 on an independent dataset. Furthermore, our model surpasses previously published works on the same dataset, thus showcasing its superior predictive capabilities.

Nucleosomal asymmetry: a novel mechanism to regulate nucleosome function.

Nucleosomes constitute the fundamental building blocks of chromatin. They are comprised of DNA wrapped around a histone octamer formed of two copies each of the four core histones H2A, H2B, H3, and H4. Nucleosomal histones undergo a plethora of posttranslational modifications that regulate gene expression and other chromatin-templated processes by altering chromatin structure or by recruiting effector proteins. Given their symmetric arrangement, the sister histones within a nucleosome have commonly been considered to be equivalent and to carry the same modifications. However, it is now clear that nucleosomes can exhibit asymmetry, combining differentially modified sister histones or different variants of the same histone within a single nucleosome. Enabled by the development of novel tools that allow generating asymmetrically modified nucleosomes, recent biochemical and cell-based studies have begun to shed light on the origins and functional consequences of nucleosomal asymmetry. These studies indicate that nucleosomal asymmetry represents a novel regulatory mechanism in the establishment and functional readout of chromatin states. Asymmetry expands the combinatorial space available for setting up complex sets of histone marks at individual nucleosomes, regulating multivalent interactions with histone modifiers and readers. The resulting functional consequences of asymmetry regulate transcription, poising of developmental gene expression by bivalent chromatin, and the mechanisms by which oncohistones deregulate chromatin states in cancer. Here, we review recent progress and current challenges in uncovering the mechanisms and biological functions of nucleosomal asymmetry.

Biologically informed NeuralODEs for genome-wide regulatory dynamics

BackgroundGene regulatory network (GRN) models that are formulated as ordinary differential equations (ODEs) can accurately explain temporal gene expression patterns and promise to yield new insights into important cellular processes, disease progression, and intervention design. Learning such gene regulatory ODEs is challenging, since we want to predict the evolution of gene expression in a way that accurately encodes the underlying GRN governing the dynamics and the nonlinear functional relationships between genes. Most widely used ODE estimation methods either impose too many parametric restrictions or are not guided by meaningful biological insights, both of which impede either scalability, explainability, or both.ResultsWe developed PHOENIX, a modeling framework based on neural ordinary differential equations (NeuralODEs) and Hill-Langmuir kinetics, that overcomes limitations of other methods by flexibly incorporating prior domain knowledge and biological constraints to promote sparse, biologically interpretable representations of GRN ODEs. We tested the accuracy of PHOENIX in a series of in silico experiments, benchmarking it against several currently used tools. We demonstrated PHOENIX’s flexibility by modeling regulation of oscillating expression profiles obtained from synchronized yeast cells. We also assessed the scalability of PHOENIX by modeling genome-scale GRNs for breast cancer samples ordered in pseudotime and for B cells treated with Rituximab.ConclusionsPHOENIX uses a combination of user-defined prior knowledge and functional forms from systems biology to encode biological “first principles” as soft constraints on the GRN allowing us to predict subsequent gene expression patterns in a biologically explainable manner.

Sex-specific developmental gene expression atlas unveils dimorphic gene networks in C. elegans

Sex-specific traits and behaviors emerge during development by the acquisition of unique properties in the nervous system of each sex. However, the genetic events responsible for introducing these sex-specific features remain poorly understood. In this study, we create a comprehensive gene expression atlas of pure populations of hermaphrodites and males of the nematode Caenorhabditis elegans across development. We discover numerous differentially expressed genes, including neuronal gene families like transcription factors, neuropeptides, and G protein-coupled receptors. We identify INS-39, an insulin-like peptide, as a prominent male-biased gene expressed specifically in ciliated sensory neurons. We show that INS-39 serves as an early-stage male marker, facilitating the effective isolation of males in high-throughput experiments. Through complex and sex-specific regulation, ins-39 plays pleiotropic sexually dimorphic roles in various behaviors, while also playing a shared, dimorphic role in early life stress. This study offers a comparative sexual and developmental gene expression database for C. elegans. Furthermore, it highlights conserved genes that may underlie the sexually dimorphic manifestation of different human diseases.

Insulin-like growth factor-1 effects on kidney development in preterm piglets.

Preterm birth disrupts fetal kidney development, potentially leading to postnatal acute kidney injury. Preterm infants are deficient in insulin-like growth factor 1 (IGF-1), a growth factor that stimulates organ development. By utilizing a preterm pig model, this study investigated whether IGF-1 supplementation enhances preterm kidney maturation. Cesarean-delivered preterm pigs were treated systemically IGF-1 or vehicle control for 5, 9 or 19 days after birth. Blood, urine, and kidney tissue were collected for biochemical, histological and gene expression analyses. Age-matched term-born pigs were sacrificed at similar postnatal ages and served as thereference group. Compared with term pigs, preterm pigs exhibited impaired kidney maturation, as indicated by analyses of renal morphology, histopathology, and inflammatory and injury markers. Supplementation with IGF-1 reduced signs of kidney immaturity, particularly in the first week of life, as indicated by improved morphology, upregulated expression of key developmental genes, reduced severity and incidence of microscopic lesions, and decreased levels of inflammatory and injury markers. No association was seen between the symptoms of necrotizing enterocolitis and kidney defects. Preterm birth in pigs impairs kidney maturation and exogenous IGF-1 treatment partially reverses this impairment. Early IGF-1 supplementation could support the development of preterm kidneys. Preterm birth may disrupt kidney development in newborns, potentially leading to morphological changes, injury, and inflammation. Preterm pigs have previously been used as models for preterm infants, but not for kidney development. IGF-1 supplementation promotes kidney maturation and alleviates renal impairments in the first week of life in preterm pigs. IGF-1 may hold potential as a supportive therapy for preterm infants sensitive to acute kidney injury.

Spatial transcriptomics in embryonic mouse diaphragm muscle reveals regional gradients and subdomains of developmental gene expression

The murine embryonic diaphragm is a primary model for studying myogenesis and neuro-muscular synaptogenesis, both representing processes regulated by spatially organized genetic programs of myonuclei located in distinct myodomains. However, a spatial gene expression pattern of embryonic mouse diaphragm has not been reported. Here, we provide spatially resolved gene expression data for horizontally sectioned embryonic mouse diaphragms at embryonic days E14.5 and E18.5. These data reveal gene signatures for specific muscle regions with distinct maturity and fiber type composition, as well as for a central neuromuscular junction (NMJ) and a peripheral myotendinous junction (MTJ) compartment. Comparing spatial expression patterns of wild-type mice with those of transgenic mice lacking either the skeletal muscle calcium channel CaV1.1 or β-catenin, reveals curtailed muscle development and dysregulated expression of genes potentially involved in NMJ formation. Altogether, these datasets provide a powerful resource for further studies of muscle development and NMJ formation in the mouse.