Biology subjects

Sun, T.

Publications and source records attributed to Sun, T..

At least 73 records · Page 4Linked to original sources

bioRxiv2023

Transposon elements shape population divergence of rice blast fungus Magnaporthe oryzae

Dynamic transposition of transposable elements (TEs) in fungal pathogens have significant impact on genome stability, gene expression, and virulence to the host. In Magnaporthe oryzae, genome plasticity resulting from TE insertion is a major driving force leading to the rapid evolution and diversification of this fungus. Despite their importance in M. oryzae population evolution and divergence, our understanding of TEs in this context remains limited. Here we conducted a genome-wide analysis of TE transposition dynamics in the 11 most abundant TE families in M. oryzae populations. Our results show that these TEs have specifically expanded in recently isolated M. oryzae rice populations, with the presence/absence polymorphism of TE insertions highly concordant with population divergence on Geng/Japonica and Xian/Indica rice cultivars. Notably, the genes targeted by clade-specific TEs showed clade-specific expression patterns and are involved in the pathogenic process, suggesting a transcriptional regulation of TEs on targeted genes. Our study provides a comprehensive analysis of TEs in M. oryzae populations and demonstrates a crucial role of recent TE bursts in adaptive evolution and diversification of the M. oryzae rice-infecting lineage. IMPORTANCEM. oryzae is the causal agent of the destructive blast disease, which caused massive loss of yield annually worldwide. The fungus diverged into distinct clades during adaptation toward two rice subspecies, Xian/indica and Geng/japonica. Although the role of TEs in the adaptive evolution was well established, mechanisms underlying how TEs promote the population divergence of M. oryzae remains largely unknown. In this study, we reported that TEs shape the population divergence of M. oryzae by differentially regulating gene expression between Xian/Indica-infecting and Geng/Japonica-infecting populations. Our results revealed a TE insertion mediated gene expression adaption that led to the divergence of M. oryzae population infecting different rice subspecies.

genomics↗

bioRxiv2023

Structure-dependent spontaneous calcium dynamics in cultured neuronal networks on microcontact-printed substrates

Microcontact printing (CP) is widely used in neuroscience research. However, CP yields reduced cell-substrate adhesion compared with directly coating cell adhesion molecules. Here, we demonstrate that the reduced cell-substrate adhesion caused by CP, high seeding density, and the local restriction would separately contribute to more aggregated (neurons closer to each other in separate clusters) neuronal networks. Calcium recordings revealed that more aggregated networks presented fewer spontaneous calcium activity patterns, and were more likely dominated by synchronized network-wide calcium oscillation (network bursts). First, on a uniform microcontact-printed substrate, densely seeded neurons were reaggregated into a Petri dish-wide network consisting of small clusters, of which the calcium dynamics were dominated by network bursts. Next, further analysis revealed this dominance was maintained since its appearance, and the initiation and propagation of bursts in the small-cluster network shared a similar mechanism with that of homogeneous networks. Then, sparsely seeded neurons formed several networks with different aggregation degrees, in which the less clustered ones presented abundant time-varying subnetwork burst patterns. Finally, by printing locally restricted patterns, highly clustered networks formed, where dominant network bursts reappeared. These findings demonstrate the existence of structure-dependent spontaneous calcium dynamics in cultured networks on microcontact-printed substrates, which provide important insights into designing cultured networks by using CP, and into deciphering the onset and evolution of network bursts in developmental nerve systems.

neuroscience↗

bioRxiv2023

Single-cell transcriptomic analyses reveal the cellular and genetic basis of aquatic locomotion in scyphozoan jellyfish

The authors have withdrawn their manuscript because the authors need to re-organize the data and writing. More experimental evidence from whole-mount ISH assay and RNAi assays will be added to support the viewpoints. Therefore, the authors do not wish this work to be cited as reference for the project. If you have any questions, please contact the corresponding author.

ecology↗

bioRxiv2023

ADAR1p150 Prevents MDA5 and PKR Activation via Distinct Mechanisms to Avert Fatal Autoinflammation

Effective immunity requires the innate immune system to distinguish foreign (non-self) nucleic acids from cellular (self) nucleic acids. Cellular double-stranded RNAs (dsRNAs) are edited by the RNA editing enzyme ADAR1 to prevent their dsRNA structure pattern being recognized as viral dsRNA by cytoplasmic dsRNA sensors including MDA5, PKR and ZBP1. A loss of ADAR1-mediated RNA editing of cellular dsRNA activates MDA5. However, additional RNA editing-independent functions of ADAR1 have been proposed, but a specific mechanism has not been delineated. We now demonstrate that the loss of ADAR1-mediated RNA editing specifically activates MDA5, while loss of the cytoplasmic ADAR1p150 isoform or its dsRNA binding activity enabled PKR activation. Deleting both MDA5 and PKR resulted in complete rescue of the embryonic lethality of Adar1p150-/- mice to adulthood, contrasting with the limited or no rescue by removing MDA5, PKR or ZBP1 alone, demonstrating that this is a species conserved function of ADAR1p150. Our findings demonstrate that MDA5 and PKR are the primary in vivo effectors of fatal autoinflammation following the loss of ADAR1p150.

genetics↗

bioRxiv2022

Interplay between acetylation and ubiquitination of imitation switch chromatin remodeler Isw1 confers multidrug resistance in Cryptococcus neoformans

Cryptococcus neoformans poses a threat to human health, but anticryptococcal therapy is hampered by the emergence of drug resistance, whose underlying mechanisms remain poorly understood. Herein, we discovered that Isw1, an imitation switch chromatin remodeling ATPase, functions as a master modulator of genes responsible for multidrug resistance in C. neoformans. Cells with the disrupted ISW1 gene exhibited profound resistance to multiple antifungal drugs. Mass spectrometry analysis revealed that Isw1 is both acetylated and ubiquitinated, suggesting that an interplay between these two modification events exists to govern Isw1 function. Mutagenesis studies of acetylation and ubiquitination sites revealed that the acetylation status of Isw1K97 coordinates with its ubiquitination processes at Isw1K113 and Isw1K441 through modulating the interaction between Isw1 and Cdc4, an E3 ligase. Additionally, clinical isolates of C. neoformans overexpressing the degradation-resistant ISW1K97Q allele showed impaired drug-resistant phenotypes. Collectively, our studies revealed a sophisticated acetylation-Isw1-ubiquitination regulation axis that controls multidrug resistance in C. neoformans.

microbiology↗

bioRxiv2022

scCDC: a computational method for gene-specific contamination detection and correction in single-cell and single-nucleus RNA-seq data

In droplet-based single-cell RNA-seq (scRNA-seq) and single-nucleus RNA-seq (snRNA-seq) assays, systematic contamination of ambient RNA molecules biases the estimation of genuine transcriptional levels. To correct the contamination, several computational methods have been developed. However, these methods do not distinguish the contamination-causing genes and thus either under- or over-corrected the contamination in our in-house snRNA-seq data of virgin and lactating mammary glands. Hence, we developed scCDC as the first method that specifically detects the contamination-causing genes and only corrects the expression counts of these genes. Benchmarked against existing methods on synthetic and real scRNA-seq and snRNA-seq datasets, scCDC achieved the best contamination correction accuracy with minimal data alteration. Moreover, scCDC applies to processed scRNA-seq and snRNA-seq data with empty droplets removed. In conclusion, scCDC is a flexible, accurate decontamination method that detects the contamination-causing genes, corrects the contamination, and avoids the over-correction of other genes.

bioinformatics↗

bioRxiv2022

Integrated transcriptome and lineage analyses reveal novel catecholaminergic cardiomyocytes contributing to the cardiac conduction system in murine heart

Cardiac conduction system (CCS) morphogenesis is essential for correct heart function yet is incompletely understood. Here we established the transcriptional landscape of cell types populating the developing heart by integrating single-cell RNA sequencing and spatial enhanced resolution omics-sequencing (Stereo-seq). Stereo-seq provided a spatiotemporal transcriptomic cell fate map of the murine heart with a panoramic field of view and in situ cellular resolution of the CCS. This led to the identification of a previously unrecognized cardiomyocyte population expressing dopamine beta-hydroxylase (Dbh+-CMs), which is closely associated with the CCS in transcriptomic analyses. To confirm this finding, genetic fate mapping by using DbhCre/Rosa26-tdTomato reporter mouse line was performed with Stereo-seq, RNAscope, and immunohistology. We revealed that Dbh+-derived CMs first emerged in the sinus venosus at E12.5, then populated the atrial and ventricular CCS components at E14.5, with increasing abundance towards perinatal stages. Further tracing by using DbhCFP reporter and DbhCreERT/Rosa26-tdTomato inducible reporter, we confirmed that Dbh+-CMs are mostly abundant in the AVN and ventricular CCS and this persists in the adult heart. By using DbhCre/Rosa26-tdTomato/Cx40-eGFP compound reporter line, we validated a clear co-localization of tdTomato and eGFP signals in both left and right ventricular Purkinje fibre networks. Finally, electrophysiological optogenetic study using cell-type specific Channelrhodopsin2 (ChR2) expression further elucidated that Dbh+-derived CMs form a functional part of the ventricular CCS and display similar photostimulation-induced electrophysiological characteristics to Cx40CreERT/ChR2-tdTomato CCS components. Thus, by utilizing advanced transcriptomic, mouse genetic, and optogenetic functional analyses, our study provides new insights into mammalian CCS development and heterogeneity by revealing novel Dbh+-CMs. HighlightsO_LIStereo-seq provided a spatiotemporal transcriptomic cell fate map of the murine heart with a panoramic field of view and in situ cellular resolution of the CCS. C_LIO_LIEstablished the transcriptional landscape of cell types populating the developing murine heart. C_LIO_LIRevealed previously unreported catecholaminergic cardiomyocyte populations contributing to the developing and mature murine cardiac conduction system. C_LI

cell biology↗

bioRxiv2022

Functional Integration of 3D-Printed Cerebral Cortical Tissue into a Brain Lesion

Engineering human tissue with diverse cell types and desired cellular architectures and functions is a considerable challenge. The cerebral cortex, which has a layered cellular architecture composed of layer-specific neurons organised into vertical columns, delivers higher cognition through intricately wired neural circuits. However, current tissue engineering approaches cannot produce such structures. Here, we use a droplet printing technique to fabricate tissues comprising simplified cerebral cortical columns. Human induced pluripotent stem cells (hiPSCs) were differentiated into upper- and deep-layer neural progenitors, which were then printed to form cerebral cortical tissues with a two-layer organization. The tissues showed layer-specific biomarker expression and developed an integrated network of processes. Implantation of the printed cortical tissues into mouse brain explants resulted in substantial implant-host integration across the tissue boundaries as demonstrated by the projection of processes, the migration of neurons and the appearance of correlated Ca2+ signals. The approach we have developed might be used for the evaluation of drugs and nutrients that promote tissue integration. Importantly, our approach might be applied in personalised implantation treatments that restore the cellular structure and function of a damaged brain by using 3D tissues derived from a patients own iPSCs.

bioengineering↗

bioRxiv2022

Flexible IrOx Neural Electrode for Mouse Vagus Nerve Stimulation

Vagus nerve stimulation (VNS) is being actively explored as a treatment for multiple conditions as part of bioelectronic medicine research. Reliable and safe VNS in mouse models is a critical need for understanding mechanisms of these. We report on the development and evaluation of a microfabricated cuff electrode (MouseFlex) constructed of polyimide (PI) and with iridium oxide (IrOx) electrodes that is thermoformed to 86 {micro}m {+/-} 12 {micro}m radius to interface the mouse cervical vagus nerve (r {approx} 50 {micro}m). Innovative bench-top methods were used to evaluated the stimulation stability and electrochemical properties of electrodes. Our aggressive stimulation stability (Stim-Stab) test utilized 1 billion pulses at a 1000 Hz with a current density of 6.28 A/cm2 (1.51 mC/cm2/phase) to evaluate electrode lifetimes, and all electrodes remained functional. We also investigated the effects of thermoforming on their impedance, charge storage capacity (CSC), and charge injection capacity (CIC). The modest changes in electrochemical properties indicate that the thermoforming process was well tolerated. Thermoformed electrode safety and efficacy were evaluated in-vivo by performing acute VNS in mice and monitoring their heart and respiration rate as biomarkers. Their electrochemical properties were also measured before, during and after VNS. Bradycardia and bradypnea were reliably induced at stimulation currents of 100 to 200 {micro}A, well below the in-vivo CIC of ~1250 {micro}A (~0.5 mC/cm2), supporting their safety and efficacy. The electrode impedance increased and CIC decreased during in-vivo use, but largely reversed these changes in in-vitro testing after enzymatic cleaning, supporting their tolerance for surgical use.

bioengineering↗

bioRxiv2022

Coupled functional physiological phenotyping and simulation model to infer the transpiration sensitivity traits and its implications for transpiration ideotype design

As agricultural drought becomes more frequent worldwide, it is essential to improve crop productivity whilst reducing the water consumption to achieve a sustainable production. Plant transpiration rate and water use efficiency (WUE) collectively determine the yield performance, yet it is challenging to balance the two in breeding programs due to still insufficient mechanistic understanding of the traits. Here we demonstrate the feasibility and effectiveness of calculating dynamic and momentary WUE by coupling WUE model and the state-of-the-art functional physiological phenotyping (FPP). We also present the method of quantifying genotype-specific traits reflecting sensitivity of transpiration to radiation (STr-Rad) and vapor pressure deficit (STr-VPD), under evolving developmental stage and water availability. Using these methods, we revealed the genotypic difference of STr-Rad and STr-VPD in three watermelon accessions, the dramatic change in each of them across the drought treatment phases, and the quantitative impacts of them on dynamic WUE patterns. Based on our results and computational simulations, a general principle for transpiration ideotype design is proposed, which highlights the benefits of lowering STr-VPD to increase WUE and increasing STr-Rad to offset the decline of Tr. FPP-enabled phenomic selection will help screen for elite crops lines with desired transpiration sensitivities.

physiology↗

bioRxiv2022

Long-term passaging of replication competent pseudo-typed SARS-CoV-2 reveals the antiviral breadth of monoclonal and bispecific antibody cocktails

The continuous emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants poses challenges to the effectiveness of neutralizing antibodies. Rational design of antibody cocktails is a realizable approach addressing viral immune evasion. However, evaluating the breadth of antibody cocktails is essential for understanding the development potential. Here, based on a replication competent vesicular stomatitis virus model that incorporates the spike of SARS-CoV-2 (VSV-SARS-CoV-2), we evaluated the breadth of a number of antibody cocktails consisting of monoclonal antibodies and bispecific antibodies by long-term passaging the virus in the presence of the cocktails. Results from over two-month passaging of the virus showed that 9E12+10D4+2G1 and 7B9-9D11+2G1 from these cocktails were highly resistant to random mutation, and there was no breakthrough after 30 rounds of passaging. As a control, antibody REGN10933 was broken through in the third passage. Next generation sequencing was performed and several critical mutations related to viral evasion were identified. These mutations caused a decrease in neutralization efficiency, but the reduced replication rate and ACE2 susceptibility of the mutant virus suggested that they might not have the potential to become epidemic strains. The 9E12+10D4+2G1 and 7B9-9D11+2G1 cocktails that picked from the VSV-SARS-CoV-2 system efficiently neutralized all current variants of concern and variants of interest including the most recent variants Delta and Omicron, as well as SARS-CoV-1. Our results highlight the feasibility of using the VSV-SARS-CoV-2 system to develop SARS-CoV-2 antibody cocktails and provide a reference for the clinical selection of therapeutic strategies to address the mutational escape of SARS-CoV-2.

cell biology↗

bioRxiv2022

Understanding water conservation vs. profligation traits in vegetable legumes through a physio-transcriptomic-functional approach

Vegetable soybean and cowpea are related warm-season legumes showing contrasting leaf water use behaviors under similar root drought stresses, whose mechanisms are not well understood. Here we conducted an integrative phenomic-transcriptomic study on the two crops grown in a feedback irrigation system that enabled precise control of soil water contents. Continuous transpiration rate monitoring demonstrated that cowpea used water more conservatively under earlier soil drought stages, but tended to maintain higher transpiration under prolonged drought. Interestingly, we observed a soybean-specific transpiration rate increase accompanied by phase shift under moderate soil drought. Time-series transcriptomic analysis suggested a dehydration avoidance mechanism of cowpea at early soil drought stage, in which the VuHAI3 and VuTIP2;3 genes were suggested to be involved. Multifactorial gene clustering analysis revealed different responsiveness of genes to drought, time of day and their interactions between the two crops, which involved species-dependent regulation of the core clock genes. Gene network analysis identified two co-expression modules each associated with transpiration rate in cowpea and soybean, including a pair of negatively-correlated modules between species. Module hub genes, including the ABA-degrading gene GmCYP707A4 and the trehalose-phosphatase/synthase gene VuTPS9 were identified. Inter-modular network analysis revealed putative co-players of the hub genes. Transgenic analyses verified the role of VuTPS9 in regulating transpiration rate under osmotic stresses. These findings propose that species-specific transcriptomic reprograming in leaves of the two crops suffering similar soil drought was not only a result of the different drought resistance level, but a cause of it.

plant biology↗

bioRxiv2022

A national professional development program fills mentoring gaps for postdoctoral researchers

The Postdoc Academy: Succeeding as a Postdoc was designed to build postdocs skills in career transition, career planning, collaborative research, resilience, and self-reflection. This study examined self-reported changes in five skills as learners progressed through the course. Data were collected from participants who responded to both pre- and post-surveys and engaged with the course learning activities. Results from repeated measures multivariate analysis of variance revealed that all of the self-reported perceptions of skills improved significantly upon completion of the course. Hierarchical regressions revealed that underrepresented minority learners had greater gains in their development of skills in career planning, resilience, and self-reflection. Qualitative analysis of learners responses to learning activities found that postdocs perceived networking and mentor support as contributing factors to their skill advancement while tensions among multiple obligations and concerns of uncertainties were significant challenges to applying those skills.

scientific communication and education↗

bioRxiv2022

Crosstalk between RNA m6A and DNA methylation regulates transposable element chromatin activation and cell fate in human pluripotent stem cells

Transposable elements (TEs) are parasitic DNA sequences accounting for over half of the human genome. Tight control of the repression and activation states of TEs is critical for genome integrity, development, immunity, and diseases, including cancer. However, precisely how this regulation is achieved remains unclear. To address this question, we develop a targeted proteomic proximity labeling approach to capture TE-associated proteins in human embryonic stem cells (hESCs). We find that the RNA N6-methyladenosine(m6A)-reader, YTHDC2, occupies genomic loci of the primate-specific TE, LTR7/HERV-H, specifically through its interaction with m6A-modified HERV-H RNAs. Unexpectedly, YTHDC2 recruits the DNA 5-methylcytosine(5mC)-demethylase, TET1, to remove 5mC from LTR7/HERV-H and prevent epigenetic silencing. Functionally, the YTHDC2/LTR7-axis inhibits neural differentiation of hESCs. Our results reveal both an underappreciated crosstalk between RNA m6A and DNA 5mC, the most abundant regulatory modifications of RNA and DNA in eukaryotes, and the fact that in hESCs this interplay controls TE activity and cell fate.

genetics↗

bioRxiv2022

GLKs directly regulate carotenoid biosynthesis via interacting with GBFs in nuclear condensates in plants

Carotenoids are vital photosynthetic pigments for plants and provide essential nutrients for humans. However, our knowledge of the regulatory control of carotenoid biosynthesis remains limited. Golden2-like transcription factors (GLKs) are widely recognized as essential and conserved factors for chloroplast development and the major regulators of chlorophyll biosynthesis. Yet the molecular mechanisms by which GLKs transcriptionally activate their target genes are unclear. Here, we report that GLKs directly regulate carotenoid biosynthesis in a G-box Binding Factor (GBF)-dependent manner. Both in vitro and in vivo studies reveal that GLKs physically interact with GBFs. Through the direct binding of GBFs to the G-box motif, the GLK-GBF regulatory module transcriptionally activates phytoene synthase (PSY), the gene encoding the rate-limiting enzyme for carotenoid biosynthesis. The ability of GLKs to promote carotenoid and chlorophyll biosynthesis is greatly diminished in the Arabidopsis gbf1/2/3 triple knockout mutants, showing the requirement of GBFs for GLK function. GLKs and GBFs form liquid-liquid phase separation-mediated nuclear condensates as the compartmented and concentrated transcriptional complexes. Our findings uncover a novel and conserved regulatory module for photosynthetic pigment biosynthesis through formation of GLK-GBF transcriptional complexes and nuclear biomolecular condensates in plants. One-sentence summaryGLKs transcriptionally regulate photosynthetic pigment synthesis in a GBF-dependent manner and are associated with the formation of phase separation-mediated nuclear condensates.

plant biology↗

bioRxiv2022

A Small Subset of Cytosolic dsRNAs Must Be Edited by ADAR1 to Evade MDA5-Mediated Autoimmunity

The innate immune system detects viral infection via pattern recognition receptors and induces defense reactions such as production of type I interferon1. One such receptor, MDA5, is activated upon the recognition of double-stranded RNAs (dsRNAs) that are often produced during viral replication2. Endogenous dsRNAs evade MDA5 activation through RNA editing by ADAR1, thus preventing autoimmunity3-5. Among the large number of endogenous dsRNAs, the key substrates whose editing is critical to evade MDA5 activation (termed as immunogenic dsRNAs) remain elusive. Here we reveal the identity of human immunogenic dsRNAs, a surprisingly small fraction of all cellular dsRNAs, to fill the gap in the ADAR1-dsRNA-MDA5 axis. We found that, in contrast to previous findings6,7, the immunogenic dsRNAs were highly enriched in mRNAs and depleted of introns, an expected indication of bona fide substrates of cytosolic MDA5. The immunogenic dsRNAs, in contrast to non-immunogenic dsRNAs, tended to have shorter loop between the stems, which may facilitate dsRNA formation. They also tended to be enriched at the GWAS signals of common inflammatory diseases, implying that they are truly immunogenic. We validated the MDA5-dependent immunogenicity of the dsRNAs, which was dampened following ADAR1-mediated RNA editing. We anticipate that a focused analysis of immunogenic dsRNAs will greatly facilitate the understanding and treatment of cancer and inflammatory diseases in which the important roles of dsRNA editing and sensing continue to be revealed8-13.

genetics↗

bioRxiv2022

Carbon oxidation with sacrificial anodes to inhibit O2 evolution in membrane-less bioelectrochemical systems for microbial electrosynthesis

Microbial electrosynthesis is an emerging biosynthesis technology that produces value-added chemicals and fuels and, at the same time, reduces the environmental carbon footprint. However, constraints, such as low current densities and high inner resistance, disfavor this technology for industrial-scale purposes. The cathode performance has been strongly improved in recent years, while the anode performance has not been given enough attention despite its importance in closing the electric circuit. For traditional water electrolysis, O2 is produced at the anode, which is toxic to the anaerobic autotrophs that engage in microbial electrosynthesis. To overcome O2 toxicity in conventional microbial electrosynthesis, the anode and the cathode chamber have been separated by an ion-exchange membrane to avoid contact between the microbes and O2. However, ion-exchange membranes increase the maintenance costs and compromise the production efficiency by introducing an additional internal resistance. Furthermore, O2 is inevitably transferred to the catholyte due to diffusion and electro-osmotic fluxes that occur within the membrane. Here, we proved the concept of integrating carbon oxidation with sacrificial anodes and microbes to simultaneously inhibit the O2 evolution reaction (OER) and circumvent membrane application, which allows microbial electrosynthesis to proceed in a single chamber. The carbon-based anodes performed carbon oxidation as the alternative reaction to the OER. This enables microbial electrosynthesis to be performed with cell voltages as low as 1.8-2.1 V at 10 A{middle dot}m-2. We utilized Methanothermobacter thermautotrophicus {Delta}H in a single-chamber Bioelectrochemical system (BES) with the best performing carbon-based anode (i.e., activated-carbon anode with soluble iron) to achieve a maximum cathode-geometric CH4 production rate of 27.3 L{middle dot}m-2{middle dot}d-1, which is equal to a volumetric methane production rate of 0.11 L{middle dot}L-1{middle dot}d-1 in our BES, at a coulombic efficiency of 99.4%. In this study, Methanothermobacter thermautotrophicus {Delta}H was majorly limited by sulfur that inhibited electromethanogenesis. However, this proof-of-concept study allows microbial electrosynthesis to be performed more energy-efficiently and can be immediately utilized for research purposes in microbial electrosynthesis.

bioengineering↗

bioRxiv2022

Maf Family Transcription Factors are Required for Nutrient Uptake in the Neonatal Gut

There are fundamental differences in the way that neonatal and adult intestines absorb nutrients. In adults, macromolecules are efficiently broken down into simpler molecular components in the lumen of the small intestine, then absorbed. In contrast, neonates are thought to rely more on bulk intake of nutrients and subsequent degradation in the lysosome. Here, we identify the Maf family transcription factors, MafB and cMaf, as markers of terminally-differentiated intestinal enterocytes throughout life. The expression of these factors is regulated by HNF4/{gamma}, master regulators of the enterocyte cell fate. Loss of Maf factors results in a neonatal-specific failure to thrive and loss of bulk uptake of nutrients. RNA-Seq and CUT&RUN analyses defined an endo-lysosomal program as being downstream of these transcription factors. We demonstrate major transcriptional changes in metabolic pathways, including fatty acid oxidation and increases in peroxisome number in response to loss of Mafs. Finally, we show that deletion of Blimp1, which represses adult enterocyte genes in the neonatal gut, shows highly overlapping changes in gene expression and similar defects in nutrient uptake. This work defines transcriptional regulators that are necessary for bulk uptake in neonatal enterocytes.

physiology↗