Biology subjects

Shukla, V.

Publications and source records attributed to Shukla, V..

At least 19 recordsLinked to original sources

bioRxiv2026

POU2AF2/OCA-T1 coactivates POU2F2 and defines a lineage-specific dependency in diffuse large B-cell lymphoma

Lineage-restricted transcriptional programs establish cell identity and can create selective dependencies in cancer. Here, we identify POU2AF2, encoding the transcriptional co-activator OCA-T1, as a critical lineage-specific dependency in a subset of diffuse large B-cell lymphoma (DLBCL). Pan-cancer dependency analyses and patient cohorts reveal elevated POU2AF2 expression in genetically aggressive DLBCL, where its depletion markedly suppresses tumor growth in vitro and in vivo. Mechanistically, POU2AF2 cooperates with the B-cell lineage-defining transcription factor POU2F2 (OCT2) to activate lymphocyte activation gene programs through direct chromatin engagement, thereby sustaining malignant transcriptional networks. We further identified a key epigenetic regulatory axis composed of the lineage-specific transcription factor TCF3 and the histone methyltransferase SET1A-COMPASS that drives POU2AF2 expression downstream of B-cell receptor signaling. Single-cell transcriptomic analysis reveals that POU2AF2 marks and sustains an innate-like B1 B-cell population in vivo, a candidate cell of origin for lymphoma. Together, these findings define a lineage-restricted POU2AF2/POU2F2 transcriptional module, controlled by a TCF3/SET1A epigenetic network, that sustains both innate-like B-cell identity and malignant fitness in DLBCL. Our study uncovers a previously unrecognized lineage-specific transcriptional dependency and highlights POU2AF2 and its associated regulatory circuitry as potential therapeutic targets in aggressive B-cell malignancies.

cell biology↗

bioRxiv2025

KDM7-mediated oxygen sensing reprograms chromatin to enhance hypoxia tolerance in the root

Roots frequently encounter low oxygen (hypoxia) from soil compaction or water saturation and must adapt to this stress. We investigated how root tip cells sense hypoxia and adjust the meristem epigenome to activate genes that promote tolerance and growth under oxygen limitation. In Arabidopsis root tips, hypoxia tolerance was linked to increased trimethylation of histone H3 at lysine 4 (H3K4me3). We also found that group 7 demethylases (KDM7s) are directly inhibited by hypoxia, and that genetic inactivation of KDM7s, like hypoxia, induces expression of genes essential for meristem survival under oxygen deprivation. We propose that KDM7s function as root-specific oxygen sensors that prime and support hypoxia tolerance.

plant biology↗

bioRxiv2025

Progressive oxygenation of developing leaves directs morphogenesis

Oxygen availability underpins energy production in multicellular organisms, yet internal oxygen gradients arise in both plants and animals. Plants sense these variations via the PLANT CYSTEINE OXIDASE branch of the N-degron pathway, which regulates the stability of key transcription factors. Originally linked to metabolic control, this pathway recently emerged as a development regulator. While the shoot apical meristem was shown to be hypoxic, the oxygen dynamics of organs originating from this low-oxygen niche remain unknown. Here we show that developing leaves form a spatiotemporal oxygen gradient that is sensed through the oxygen sensing machinery. This pathway integrates local oxygen availability to regulate leaf morphogenesis: early hypoxia restricts cell expansion, while subsequent distal-to-proximal oxygenation enables specialized cell fates acquisition. Our findings reveal that oxygen acts as a positional cue in normal growth, guiding developmental trajectories. Our work highlights opportunities to harness oxygen gradients or sensing to direct plant form and function.

plant biology↗

bioRxiv2025

Anatomy and habitat shape the oxygen sensing machinery of angiosperms

Hypoxia sensing via the Cys/Arg branch of the N-degron pathway (Cys-NDP) is central for flooding responses in plants, yet how evolutionary and ecological factors have shaped the core oxygen sensing mechanism remains poorly understood. Leveraging the publication of multiple angiosperm genomes, we systematically analysed known Cys-NDP components in 55 angiosperms spanning aquatic, epiphytic, xerophytic, and mesophytic lineages. We also complemented this survey with hypoxia profiling and transcriptomic analyses in a selected panel of plants. This comparative effort revealed variation in Cys-NDP components, with Plant Cysteine Oxidases (PCOs) and group VII Ethylene Response Factors (ERFVIIs) emerging as major sources of diversification. Aquatic monocots displayed complete loss of A-type PCOs and dramatic expansion of a novel clade of ERFVIIs (HREaqua), frequently accompanied by loss or modification of the Cys-degron, uncoupling them from oxygen-dependent turnover. By contrast, xerophytes and epiphytes retained core Cys-NDP elements but showed shared hypoxia-induced gene expression, suggesting endogenous developmental or metabolic pressures for pathway conservation in habitats with limited flooding risk. Across all species, we identified a conserved transcriptional core of 11 orthogroups, including fermentation enzymes and regulatory factors, highlighting the early recruitment of these genes to hypoxia responses. Functional assays confirmed contributions of conserved MYB and LBD transcription factors to hypoxia tolerance in Arabidopsis. Together, our results demonstrate that both habitat and anatomy influence the evolution and deployment of oxygen-sensing networks in angiosperms. While persistent submergence promoted diversification of ERFVIIs and PCOs, retention of the core pathway across lineages points to fundamental roles in coping with endogenous oxygen gradients and fluctuations.

plant biology↗

bioRxiv2025

TPS Proteins coordinate plant growth with sugar availability via the SnRK1 Kinase

The ability to sense and respond to nutrients determines adaptation and survival in all organisms. In plants, sucrose stimulates growth and developmental progression via the signalling sugar trehalose 6-phosphate (T6P) which reflects sucrose availability. T6P acts, at least partly, by inhibiting the protein kinase SUCROSE NON-FERMENTING 1 (SNF1)-RELATED KINASE 1 (SnRK1) but the underlying mechanisms are poorly understood. Here, we identify a group of catalytically inactive T6P synthase (TPS) proteins, TPS5/6/7, as important factors for coupling the T6P signal to SnRK1 activity. In Arabidopsis thaliana, lack of TPS5/6/7 causes severe growth defects, particularly in roots. This is accompanied by a metabolic signature that is suggestive of T6P insensitivity and impaired sucrose utilization. Using a combination of genetics, SnRK1 activity assays, and imaging, we demonstrate that the growth defects of the tps5/6/7 mutant are due to SnRK1 misregulation and are reverted by knocking-down SnRK1 in this background. Co-immunoprecipitation assays further show that T6P promotes the interaction of TPS proteins with SnRK1 in a highly specific and dose-dependent manner. Our results support a model where TPS proteins act as T6P sensors, inhibiting non-nuclear SnRK1 activity when sucrose is abundant to promote biosynthetic processes and growth.

plant biology↗

bioRxiv2025

Systematic analysis of lectin gene family reveals dynamic modes of paralogue evolution and immune regulatory functions in tomato

Lectins are a structurally diverse class of carbohydrate-binding proteins implicated in plant development and stress responses. In this study, we present a comprehensive structural, evolutionary, and functional analysis of the lectin gene family in tomato (Solanum lycopersicum cv. Heinz). We identified 247 lectin genes across eight major families, exhibiting diverse domain architectures, including merolectins, hololectins, and chimerolectins. Gene ontology enrichment, tissue-specific expression profiling, and stress-responsive transcriptomics highlighted key roles of lectin genes in development and pathogen defense. Comparative genomic analyses across five Solanum species and ancestral outgroups (Vitis vinifera and Amborella trichopoda) revealed both conserved and lineage-specific expansions driven by whole-genome and small-scale duplications. Evolutionary modeling indicated that most lectin gene duplications are under purifying selection, with some genes exhibit signatures of adaptive evolution. Expression and co-expression variance among duplicated paralogues revealed three distinct evolutionary fates -balance, dominance, and divergence. Notably, small-scale duplications frequently led to functional divergence, whereas whole-genome duplicates largely retained ancestral expression patterns. Functional validation through virus-induced gene silencing (VIGS) of two GNA chimerolectins, Solyc04g077390 and Solyc07g063700, revealed their role as negative regulators of immunity. Silencing these genes enhanced resistance to Ralstonia solanacearum, reduced bacterial colonization, and triggered stronger induction of defense-related genes. Together, these findings highlight the structural innovation, evolutionary dynamics, and immune regulatory roles of lectin genes in tomato, and identifies promising targets for breeding disease-resistant cultivars in Solanum lycopersicum and related crops.

plant biology↗

bioRxiv2025

Engineering reduced activity in the oxygen-sensing Arabidopsis thaliana plant cysteine oxidase 4 enzyme results in improved flood resilience

Plant cysteine oxidases (PCOs) are O2-sensing enzymes that play an important role in plant responses to low oxygen (hypoxia). PCO-catalysed dioxygenation of the N-terminal Cys of substrates, including Group VII Ethylene Response Factors (ERVIIs), targets them for degradation via the Cys/Arg N-degron pathway, however these substrates are stabilized in hypoxia due to reduced PCO activity. When plants are flooded, submergence-induced hypoxia results in ERFVII-mediated upregulation of hypoxia responsive genes that reconfigure plant metabolism and allow short-term resilience to the conditions. However, the increasing frequency and duration of flood events requires strategies to improve plant flood resilience, particularly amongst agronomic crops. One possibility is to prolong the stability of ERFVIIs by engineering the PCOs to catalyse their oxidation less efficiently. We report a structure-guided kinetic and biophysical investigation of Arabidopsis thaliana PCO4 that reveals residues important for substrate-binding and catalysis. We subsequently selected AtPCO4 variants Y183F and C173A, with severe and mild impacts on AtPCO4 activity, respectively, to complement Arabidopsis pco1pco2pco4pco5 plants and investigate their impact on submergence resilience. Both variants appeared to be beneficial for survival and recovery after 2.5 and 3.5 days of dark submergence when compared to control plants, indicating that engineering PCOs can be used as a strategy to improve flood tolerance in plants.

plant biology↗

bioRxiv2025

Conservation of chromatin states and their association with transcription factors in land plants

The complexity of varied modifications of chromatin composition is integrated in archetypal combinations called chromatin states that predict the local potential for transcription. The degree of conservation of chromatin states has not been established amongst plants, and how they interact with transcription factors is unknown. Here we identify and characterize chromatin states in the flowering plant Arabidopsis thaliana and the bryophyte Marchantia polymorpha, showing a large degree of functional conservation over more than 450 million years of land plant evolution. We used this new resource of conserved plant chromatin states to understand the influence of chromatin states on gene regulation. We established the preferential association of chromatin states with binding sites and activity of transcription factors. These associations define three main groups of transcription factors that bind upstream of the transcription start site, at the +1 nucleosome or further downstream of the transcription start site and broadly associate with distinct biological functions. The association with the +1 nucleosome defines a list of candidate pioneer factors we know little about in plants, compared to their important roles in animal stem cells and early development.

genomics↗

bioRxiv2025

Clade I TGA transcription factors are negative regulators of sulfate uptake and metabolism

Increasing crop nutrient use efficiency can have dual impact; it can significantly reduce costs for fertilizers and mitigate global environmental repercussions caused by nutrient leakage. Understanding nutrient crosstalk in light of global environmental changes is crucial for improving nutrient use efficiency and food security. Here we show that provision of nitrate, but not ammonium, induces sulfate uptake and assimilation. We reveal that TGA1 and TGA4 are negative regulators of sulfate uptake, while other TGAs and the nitrate receptors NRT1.1 and NLP7 are not involved in this regulation. Our results show that TGA1 and TGA4 negatively regulate a larger set of genes involved in S signaling and metabolism, not only under nitrate provision, but also under S-deficiency. Under long-term S-deficiency, tga1 tga4 mutant had increased Cys levels in the shoots and showed better fitness. Additionally, TGA1 and TGA4 play a negative role in pathogen-induced indolic GSLs synthesis under sulfate deficiency. Similarly, clade I TGA TFs negatively regulate camalexin accumulation under pathogenic bacteria infection. Together, our findings suggest that TGA1 and TGA4 play an important role in the crosstalk of nitrate signaling with sulfate metabolism, and affect the function of S-metabolites in the interaction with pathogenic bacteria.

plant biology↗

bioRxiv2025

Rate Limiting Enzymes in Nucleotide Metabolism Synchronize Nucleotide Biosynthesis and Chromatin Formation

Chromatin formation requires both an adequate nucleotide supply and sufficient availability of histones. Chromatin must be assembled following DNA-based fundamental cellular processes such as replication and transcription to preserve genome integrity. Chromatin assembly is regulated by the orderly engagement of histones with a series of histone chaperones that guide newly synthesized histones from ribosomes to DNA. Although the synthesis of nucleotides and the histone proteins are the two major biosynthetic processes that complete the formation of chromatin, how these processes are coordinated remains unknown. Phosphoribosyl pyrophosphate synthetases (PRPSs) catalyze the first and rate-limiting step in the nucleotide biosynthesis pathway. PRPS enzymes form a complex with PRPS-associated proteins (PRPSAPs). In the present study, we discover that PRPS-PRPSAP enzyme complex are part of histone chaperone network. We show that PRPS enzymes are essential not only for nucleotide biogenesis, but together with PRPSAP also play a key role in the early steps in the process of histone maturation by regulating the interaction of histone chaperones with histone H3 and H4. Importantly, this regulation is separate from PRPS nucleotide biosynthetic activity. Depletion of PRPS proteins leads to limited histone availability and impaired chromatin assembly. Our discovery bridges cellular metabolism and chromatin regulation and provides the evidence of how nucleotide biogenesis and histone deposition are coordinated.

cell biology↗

bioRxiv2025

GWAs reveals SUBER GENE1-mediated suberization via Type One Phosphatases

Suberin deposition in the root endodermis is critical for plant nutrient acquisition and environmental adaptation. Here, we used an unbiased forward genetic approach based on natural variation across 284 Arabidopsis thaliana accessions to identify novel regulators of endodermal suberization. This screen revealed striking diversity in suberin levels and patterns, uncovering broader roles for suberin beyond those observed in the reference accession Col-0. A genome-wide association study pinpointed SUBER GENE1 (SBG1), a previously uncharacterized gene encoding a 129-amino acid protein, as a key regulator of suberin deposition. SBG1 acts through physical interaction with type one protein phosphatases (TOPPs) via conserved SILK and RVxF motifs. Disrupting this interaction abolishes SBG1 function, while topp mutants exhibit enhanced endodermal suberization, mirroring SBG1 overexpression. Our findings uncover a previously unknown regulatory module linking suberin formation to TOPP activity and ABA signaling and provide a framework for improving plant stress resilience through targeted manipulation of root barrier properties.

plant biology↗

bioRxiv2025

CTCF directly binds G-quadruplex structures to regulate genome topology and gene expression

DNA G-quadruplexes (G4s) are non-B form secondary DNA structures that are highly conserved across evolution. G4 structures occupy key regulatory sites in the mammalian genomes and are implicated in several cellular processes. However, the mechanisms by which G4s contribute to distinct facets of genome function are not well understood. Here, we conduct a proteomics screen with G4s of diverse topologies to uncover novel G4 binding activities in genomic regulators of nucleosome remodeling, paraspeckle assembly, RNA splicing, and 3D genome organization. Among the most prominent hits, we identify the genomic architectural protein, CTCF, as one of the strongest G4 binders. Building on this discovery, we perform extensive biochemical validation of CTCF-G4 interaction and identify CTCF mutants, with pronounced affinity for G4s over its consensus DNA motif. By implementing well-established approaches and developing new G4 mapping tools, we define a comprehensive catalog of genomic G4s and investigate their association with CTCF binding. Using genetic reconstitution of mouse embryonic stem cells with a G4-specific CTCF mutant, we ascribe genomic functions to CTCF-G4 interactions in regulation of CTCF occupancy, chromatin looping and gene expression. Interestingly, our studies reveal a subset of G4-linked chromatin loop anchors that form "persistent loops" which are retained even upon CTCF depletion. Collectively, our work establishes the G4 binding activity of CTCF and provides new insights into the functional significance of G4 structures.

molecular biology↗

bioRxiv2025

Integrative spatial transcriptomic analysis pinpoints the role of TaMCO3 encoding ferroxidase in wheat root tip iron mobilization

Roots play an critical role in the sensing and absorption of essential minerals from the rhizosphere. Iron (Fe) deficiency, for example, triggers a well-known series of physiological and molecular responses within roots that facilitate uptake, which differs between monocots and dicots. In monocots, little is known about molecular responses that occur within specific root development zones in response to iron deprivation, and how these differences results in overall nutrient uptake. Here, we conducted a transcriptome analysis of wheat root tips under Fe deficiency (-Fe) and performed a comparative transcriptome analysis with the previous datasets generated from the whole root. Gene ontology analysis of differentially expressed genes highlighted the significance of oxidoreductase activity and metal/ion transport in the root tip, which are critical for Fe mobilisation. Interestingly, wheat, an allohexaploid species consisting of three different genomes (A, B, and D) displayed varying gene expression levels arising from the three genomes that contributed to similar molecular functions. Detailed analysis of oxidoreductase function at the root tip revealed multiple multi-copper oxidase (MCO) proteins, such as Fe-responsive TaMCO3, that likely contribute to the overall ferroxidase activity. Detailed characterisation of TaMCO3 shows that it complements the yeast FET3 mutant and rescues the -Fe sensitivity phenotype of Arabidopsis atmco3 mutants by enhancing vascular Fe loading. Transgenic wheat lines overexpressing TaMCO3 exhibited increased root Fe accumulation and improved tolerance to -Fe by augmenting the expression of Fe-mobilizing genes. Our findings highlight the role of spatially resolved gene expression in -Fe responses, suggesting strategies to reprogram cells for improved nutrient stress tolerance.

plant biology↗

bioRxiv2024

Engineering prolyl hydroxylase-dependent proteolysis enables the orthogonal control of hypoxia responses in plants

Vascular plants and metazoans use selective proteolysis of transcription factors to control the adaptive responses to hypoxia, although through distinct biochemical mechanisms. The reason for this divergence is puzzling, especially when considering that the molecular components necessary to establish both strategies are conserved across the two kingdoms. To explore an alternative evolutionary scenario where plants sense hypoxia as animals do, we engineered a three-components system aimed to target proteins for degradation in an oxygen dependent manner in Arabidopsis thaliana. Applying the synthetic biology framework, we produced a hypoxia-responsive switch independent of endogenous pathways. When applied to control transcription, the synthetic system partially restored hypoxia responsiveness in oxygen-insensitive mutants. Additionally, we demonstrated its potential to regulate growth under flood-induced hypoxia. Our work highlights the use of synthetic biology to reprogram signalling pathways in plants, providing insights into the evolution of oxygen sensing and ofering tools for crop improvement under stress conditions.

synthetic biology↗

bioRxiv2024

H2O2 repurposes the plant oxygen-sensing machinery to control the transcriptional response to oxidative stress

Plants sense reduced oxygen availability (hypoxia) through Plant Cysteine Oxidases (PCOs). Reduced PCO activity in hypoxia, as seen during submergence, stabilises Group VII Ethylene Response Factors (ERFVIIs), master regulators of adaptive metabolic and anatomic responses. Equally important is timely arrest of these responses upon reoxygenation, assumed to occur through ERFVII degradation. Reoxygenation involves reactive oxygen species (ROS) production. Here, we report that instead of degradation, reoxygenation results in ERFVII nuclear stabilisation, an effect mimicked by direct H2O2 treatment. Interestingly, typical hypoxia marker genes are repressed while genes involved in ROS homeostasis and oxidative stress protection are upregulated. Using in planta, heterologous and biochemical assays, we reveal that ROS-related ERFVII stabilisation is caused by PCO inactivation. Stabilised ERFVIIs are retained at hypoxia-responsive promoters but become repressors. Our findings suggest that by responding to both oxygen and ROS, PCOs coordinate ERFVII stability to regulate timely responses to damaging fluctuations in oxygen availability.

plant biology↗

bioRxiv2024

DDX41 dissolves G-quadruplexes to maintain erythroid genome integrity and prevent cGAS-mediated cell death

Deleterious germline DDX41 variants constitute the most common inherited predisposition disorder linked to myeloid neoplasms (MNs). The role of DDX41 in hematopoiesis and how its germline and somatic mutations contribute to MNs remain unclear. Here we show that DDX41 is essential for erythropoiesis but dispensable for the development of other hematopoietic lineages. Using stage-specific Cre models for erythropoiesis, we reveal that Ddx41 knockout in early erythropoiesis is embryonically lethal, while knockout in late-stage terminal erythropoiesis allows mice to survive with normal blood counts. DDX41 deficiency induces a significant upregulation of G-quadruplexes (G4), noncanonical DNA structures that tend to accumulate in the early stages of erythroid precursors. We show that DDX41 co-localizes with G4 on the erythroid genome. DDX41 directly binds to and dissolves G4, which is significantly compromised in MN-associated DDX41 mutants. Accumulation of G4 by DDX41 deficiency induces erythroid genome instability, defects in ribosomal biogenesis, and upregulation of p53. However, p53 deficiency does not rescue the embryonic death of Ddx41 hematopoietic-specific knockout mice. In parallel, genome instability also activates the cGas-Sting pathway, which is detrimental to survival since cGas-deficient and hematopoietic-specific Ddx41 knockout mice are viable without detectable hematologic phenotypes, although these mice continue to show erythroid ribosomal defects and upregulation of p53. These findings are further supported by data from a DDX41 mutated MN patient and human iPSC-derived bone marrow organoids. Our study establishes DDX41 as a G4 dissolver, essential for erythroid genome stability and suppressing the cGAS-STING pathway.

cancer biology↗

bioRxiv2024

The role of ERFVIIs as oxygen-sensing transducers in the evolution of land plant response to hypoxia

The transcriptional response to low oxygen (hypoxia) in the flowering plant Arabidopsis thaliana is transduced through group VII Ethylene Response Factor (ERFVII) transcription factors, whose proteolysis is oxygen-dependent via the PLANT CYSTEINE OXIDASE (PCO) N-degron pathway. When and how this response to hypoxia evolved in land plants remains unknown. Here we investigated the conservation and divergence of transcriptional responses to hypoxia in major land plant clades. We identified induction of gene functions associated with glycolysis and fermentation as part of a conserved response across all land plant divisions. Our results indicate that ERFVIIs appeared in the last common ancestor of vascular plants with true roots, concurrently with oxygen-dependent destabilisation, to regulate hypoxia-adaptive genes. Proteins from other ERF groups have been recruited multiple times in different clades as substrates of the PCO N-degron pathway. Our results demonstrate that the response of land plants to hypoxia has been refined in derived clades through the evolution of ERFVIIs as transcriptional transducers, that occurred concomitantly with the appearance of vascular systems and roots as foraging systems through hypoxic soil.

plant biology↗

bioRxiv2024

Effects Of Aryl Hydrocarbon Receptor Ligand TCDD On Human Trophoblast Cell Development

STUDY QUESTIONHow does activation of AHR signaling affect human trophoblast cell development and differentiation? SUMMARY ANSWERAHR activation leads to altered gene expression but does not hinder the ability of trophoblast cells to remain in a stem cell state or differentiate into essential cell types, such as extravillous trophoblast cells (EVT) or syncytiotrophoblast (ST). It also promotes the production of 2 methoxy estradiol (2ME), a compound that could influence placental development. WHAT IS KNOWN ALREADYThe placenta serves both as a nutrient delivery system and a protective barrier against environmental toxins. AHR signaling is known to mediate cellular responses to environmental pollutants, potentially affecting trophoblast cell functions, but the specific impacts of AHR activation on these cells were not fully understood. STUDY DESIGN, SIZE, DURATIONThis study utilized an in vitro model of human trophoblast stem (TS) cells to investigate the downstream effects of AHR activation. The study focused on both undifferentiated TS cells and cells undergoing differentiation. PARTICIPANTS/MATERIALS, SETTING, METHODSHuman trophoblast stem (TS) cells were used as the model system. Researchers examined the effects of TCDD exposure in both TS cells maintained in their stem state and those induced to differentiate into EVT or ST. The study assessed changes in gene expression, particularly focusing on CYP1A1 and CYP1B1, as well as the production of 2ME. MAIN RESULTS AND THE ROLE OF CHANCEAHR activation stimulated the expression of CYP1A1 and CYP1B1, key genes associated with AHR signaling, in both undifferentiated and differentiating trophoblast cells. While AHR activation did not impact the cells ability to remain in a stem state or differentiate, it increased the production of 2ME, which may influence placental function. These effects were dependent on AHR signaling. LIMITATIONS, REASONS FOR CAUTIONThis study was conducted in vitro, which may not fully replicate human conditions. Further research is needed to confirm whether these findings apply to actual placental development in humans. WIDER IMPLICATIONS OF THE FINDINGSThe results suggest that AHR signaling activated by environmental pollutants could have a subtle but significant impact on placental development through mechanisms involving AHR activation. These findings may have broader implications for understanding how environmental factors affect fetal development. STUDY FUNDING/COMPETING INTEREST(S)This work was funded by the National Institutes of Health: ES028957, HD020676, ES029280, HD105734 and the Sosland Foundation. The authors declare no conflicts of interest.

developmental biology↗