Biology subjects

Braud, M.

Publications and source records attributed to Braud, M..

9 recordsLinked to original sources

bioRxiv2026

The PGC-1α Gly482Ser rs8192678 SNP reprograms oxidative metabolism to favor energy storage in females

The Gly482Ser SNP (rs8192678) in the peroxisome proliferator-activated receptor gamma coactivator 1 alpha (PPARGC1A) gene has been associated with obesity, type 2 diabetes and other human metabolic diseases. In this study, we found that human iPSCs carrying a serine risk allele had reduced respiratory capacity, and individuals living with overweight or obesity homozygous for the serine allele (S/S) exhibited a preference for carbohydrate oxidation following a high-fat meal. Using a PGC-1Ser481Gly knock-in mouse model, we performed metabolic phenotyping of male and female mice carrying the three genotypes (G/G, S/G, S/S) under acute nutritional challenges (chow, fasting and high-fat high-sugar (HFHS) feeding) and chronic HFHS feeding. S/S females were heavier and showed a trend toward an increased respiratory exchange ratio (RER) during fasting, with greater weight gain and fat mass following chronic HFHS feeding. Transcriptomic analyses revealed tissue-specific reprogramming of mitochondrial oxidative pathways, that were downregulated in subcutaneous adipose tissue and liver while upregulated in muscle, with the strongest effects observed in S/S females. Together, these findings provide in vivo evidence that this SNP reprograms whole-body oxidative metabolism, with a net effect of favoring carbohydrate oxidation and energy conservation, particularly in females.

physiology↗

bioRxiv2026

A JAK-STAT-activated myeloid hub at ulceration sites underlies resistance to anti-TNF therapy in Crohn's disease

Despite major advances in immunotherapies, durable disease control in immune-mediated inflammatory diseases (IMIDs) is frequently limited by resistance driven by maladaptive immune programs, resulting in progressive tissue damage. Myeloid cells are central effectors across IMIDs, including inflammatory bowel disease (IBD), yet how discrete myeloid states govern disease progression and therapeutic response remains incompletely defined. Here, using integrative single-cell transcriptomic and molecular analyses of inflamed human ileum in Crohns disease (CD), we identify combinatorial transcriptional programs that revealed previously unrecognized axes of monocyte-macrophage (mo-mac) heterogeneity. These myeloid states and programs were conserved and validated across multiple independent cohorts. We delineate a pathogenic mo-mac subset, interferon-associated inflammatory monocytes (IFIM), shaped by convergent NF-{kappa}B and IFN{gamma} signaling and enriched in advanced disease. Baseline abundance of IFIM programs predicted resistance to anti-TNF therapy and severe postoperative recurrence, with IFIM-derived ligands sustaining epithelial injury. IFIM exhibited robust JAK-STAT activation, indicating susceptibility to JAK inhibition with clinically approved agents, including upadacitinib. Exemplified by IFIM-driven inflammation, these findings identify pathogenic myeloid state remodeling as a molecular basis of anti-TNF resistance and provide a framework for mechanism-guided therapeutic strategies across chronic inflammatory diseases.

immunology↗

bioRxiv2025

A core genetic mechanism integrates growth hormone signals to control meristem fate and inflorescence architecture in setaria and maize

Inflorescence architecture in cereals is a major determinant of grain yield and harvestability. Architecture is determined by the number, arrangement and order of lateral branches, which are formed from clusters of stem cells called meristems. Variation in branching patterns arises from regulation of meristem determinacy, i.e., indeterminate meristems maintain meristematic activity allowing for higher order branching and determinate meristems form a terminal organ. The timing by which an indeterminate branch meristem acquires a determinate fate and transitions to a spikelet meristem (SM), ultimately forming the grain-bearing spikelet, defines architecture and grain yield potential. This study leverages the unique inflorescence morphology of model grass Setaria viridis (setaria) to identify factors controlling SM fate and determinacy and characterize their interactions. In setaria, axillary branches terminate either in a spikelet or sterile bristle, where the latter loses SM identity due to brassinosteroid (BR)-mediated disruption of organ boundary formation. A forward genetics screen identified two mutants with only bristles on their panicles; one defective in gibberellic acid (GA) signaling caused extreme elongation and disruption of spikelet development and the other homeotically converted spikelets to bristles. The latter named spikeletless (spkl) was mapped and validated as an ortholog of the maize determinacy factor ramosa1 (ra1). Genetic analyses showed that SvRa1 acts upstream of BR-mediated regulation of SM identity and determinacy. A model is proposed where SvRA1 maintains SM fate by modulating GA homeostasis, spatially restricting BR signaling and preserving boundary gene expression and determinacy. In bristle primordia, which are generally paired with spikelets, GA and BR act synergistically. Comparative analyses in maize highlight pathway conservation in inflorescence architecture with some specific variations.

plant biology↗

bioRxiv2024

TDG orchestrates ATF4-dependent gene transcription during retinoic acid-induced cell fate acquisition

Acquisition of cell identity is associated with a remodeling of the epigenome in part through active DNA demethylation. The T:G mismatch DNA glycosylase (TDG) participates to this process by removing 5-methylcytosines that have been oxidized by Ten-Eleven-Translocation (TET) enzymes. Despite this well-defined molecular function, a comprehensive view of the biological function of TDG is still lacking, especially during cell differentiation. Here, we combined transcriptomic and epigenomic approaches in a Tdg knock-out epiblast stem-like cell model to decipher TDG function in pluripotent cells and their retinoic acid-induced progeny. We determined that TDG occupies a majority of active promoters, a large fraction of which are also engaged by the transcription factor ATF4. Consistently, neural fate commitment upon retinoic acid treatment is associated with a TDG-dependent sustained expression of ATF4-dependent genes, in relation with a TDG-associated nucleosome positioning at promoters. We further evidenced that TDG maintains ATF4 pathway activity by positively regulating the mammalian target of rapamycin complex 1 (mTORC1), favoring neural cell fate commitment. These observations highlight the central role of TDG in cell differentiation and support a model linking metabolic reprogramming to cell fate acquisition.

genomics↗

bioRxiv2024

Transcriptomic, clonal, and functional analyses reveal Liver tissue-imprinted immuno-profile of circulating autoreactive CD4 T cells in autoimmune liver diseases

Autoimmune liver diseases (AILD) are immune-mediated disorders in which CD4 T cells play a central role. However, the link between circulating self-antigen-specific CD4 T cells and the targeted tissue has not been extensively studied in AILD. We hypothesized that circulating autoreactive CD4 T cells were clonally and functionally related to dominant intra-hepatic pathogenic CD4 T cell clones. Single cell transcriptomic analysis of circulating self-antigen-specific CD4 T cells revealed a specific B-helper and immuno-exhausted transcriptional profile, which was conserved for different autoantigens, but distinct from several other types of foreign antigen specificities. In the blood, the dominant hepatic CD4 T cell clones had a similar transcriptomic signature and were enriched in the PD-1+ TIGIT+ HLA-DR+ CD4 T cell subset. In a mouse model, antigen-specific CD4 T cells acquired the immuno-exhausted transcriptional profile when they accumulated in the liver after local antigen reactivity. Locally, immune checkpoint molecules controlled the response of antigen-specific CD4 T cells responsible for liver damage. Our study reveals the origin and biology of liver-derived autoreactive CD4 T cells in the blood of AILD patients that are imprinted by the liver environment, and suggest a dysregulation of the immune checkpoint molecules pathways. Our study enables tracking and isolating circulating autoreactive CD4 T cells for future diagnostic and therapeutic purposes.

immunology↗

bioRxiv2023

Regulatory variation controlling architectural pleiotropy in maize

An early event in plant organogenesis is establishment of a boundary between the meristem and differentiating lateral organ. In maize (Zea mays), evidence suggests a common gene network functions at boundaries of distinct organs and contributes to pleiotropy between leaf angle and tassel branch number, two agronomic traits. To uncover regulatory variation at the nexus of these two traits, we used regulatory network topologies derived from specific developmental contexts to guide multivariate genome-wide association analyses. In addition to defining network plasticity around core pleiotropic loci, we identified new transcription factors that contribute to phenotypic variation in canopy architecture, and structural variation that contributes to cis-regulatory control of pleiotropy between tassel branching and leaf angle across maize diversity. Results demonstrate the power of informing statistical genetics with context-specific developmental networks to pinpoint pleiotropic loci and their cis-regulatory components, which can be used to fine-tune plant architecture for crop improvement.

plant biology↗

bioRxiv2021

High Light and High Temperature Reduce Photosynthesis via Different Mechanisms in the C4 Model Setaria viridis

C4 plants frequently experience damaging high light (HL) and high temperature (HT) conditions in native environments, which reduce growth and yield. However, the mechanisms underlying these stress responses in C4 plants have been under-explored, especially the coordination between mesophyll (M) and bundle sheath (BS) cells. We investigated how the C4 model plant Setaria viridis responded to a four-hour HL or HT treatment at the photosynthetic, transcriptomic, and ultrastructural levels. Although we observed a comparable reduction of photosynthetic efficiency in HL- or HT-treated leaves, detailed analysis of multi-level responses revealed important differences in key pathways and M/BS specificity responding to HL and HT. We provide a systematic analysis of HL and HT responses in S. viridis, reveal different acclimation strategies to these two stresses in C4 plants, discover unique light/temperature responses in C4 plants in comparison to C3 plants, and identify potential targets to improve abiotic stress tolerance in C4 crops.

plant biology↗

bioRxiv2020

Regulatory signatures of drought response in stress resilient Sorghum bicolor

The effects of drought stress can be devastating to crop production worldwide. A grand challenge facing agriculture is development of crop varieties with improved drought resilience through breeding or biotechnology. To accelerate this, a mechanistic understanding is needed of the regulatory networks underlying drought response in crop genomes and the genetic elements that modulate them. Here, we explore the regulatory landscape of sorghum [Sorghum bicolor (L.) Moench] in response to controlled-environment drought stress. Sorghum is a C4 cereal crop with innate drought resilience. To define molecular signatures of drought response, we mapped genome-wide chromatin accessibility using an Assay for Transposase Accessible Chromatin by sequencing and analyzed parallel transcriptional profiles in drought-stressed sorghum shoot and root tissues. Drought-responsive changes in accessibility were largely in proximal promoters of differentially expressed genes and also in distal regions. Data were integrated to infer gene network connections and cis-regulatory modules underlying drought response and the transcription factors that control them. Inspection of pan-genomic data and phenotyping across sorghum diversity revealed variation in genomic signatures that associated with water use efficiency. Our analyses provide drought-inducible regulatory modules in sorghum that can be leveraged for fine-tuning responses to stress, mining for advantageous alleles, and translating across species.

plant biology↗

bioRxiv2020

SvFUL2, an A-class MADS-box transcription factor, is necessary for inflorescence determinacy in model panicoid cereal, Setaria viridis

Inflorescence architecture in cereal crops directly impacts yield potential through regulation of seed number and harvesting ability. Extensive architectural diversity found in inflorescences of grass species is due to spatial and temporal activity and determinacy of meristems, which control the number and arrangement of branches and flowers, and underlie plasticity. Timing of the floral transition is also intimately associated with inflorescence development and architecture, yet little is known about the intersecting pathways and how they are rewired during development. Here, we show that a single mutation in a gene encoding an AP1 A-class MADS-box transcription factor significantly delays flowering time and disrupts multiple levels of meristem determinacy in panicles of the C4 model panicoid grass, Setaria viridis. Previous reports of A-class genes in cereals have revealed extensive functional redundancy, and in panicoid grasses, no associated inflorescence phenotypes have been described. In S. viridis, perturbation of SvFul2, both through chemical mutagenesis and CRISPR/Cas9-based gene editing, converted a normally determinate inflorescence habit to an indeterminate one, and also repressed determinacy in axillary branch and floral meristems. Our analysis of gene networks connected to disruption of SvFul2 identified regulatory hubs at the intersect of floral transition and inflorescence determinacy, providing insights into the optimization of cereal crop architecture.

plant biology↗