Biology subjects

Jackson, V.

Publications and source records attributed to Jackson, V..

5 recordsLinked to original sources

bioRxiv2025

Metagenomics of the MAST-3 stramenopile, Incisomonas, and its associated microbiome reveals unexpected metabolic attributes and extensive nutrient dependencies

Protists are polyphyletic singled-celled eukaryotes that underpin global ecosystem functioning, particularly in the oceans. Most remain uncultured, limiting investigation of their physiology and cell biology. MArine STramenopiles (MASTs) are heterotrophic protists that, although related to well-characterised photosynthetic diatoms and parasitic oomycetes, are poorly studied. The Nanomonadea (MAST-3) species Incisomonas marina has been maintained in co-culture with a bacterial consortium, offering opportunities to investigate the metabolic attributes and nutritional dependencies of the community. Employing a metagenomics approach, the 68 Mbp haploid genome of I. marina was retrieved to an estimated completeness of 93%, representing the most complete MAST genome so far. We also characterised the diversity of, and assembled genomes for, 23 co-cultured bacteria. Auxotrophy of I. marina for B vitamins (B1, B2, B6, B7 and B12), but not vitamins C, B3, B5 and B9 was predicted. Several bacteria also lacked complete B-vitamin biosynthesis pathways, suggesting that vitamins and/or their precursors are exchanged in the consortium. Moreover, I. marina lacked the ability to synthesise half the protein amino acids, although genes encoding the complete urea cycle were identified, like diatoms; this may play a role in recycling organic nitrogen compounds. Unexpectedly, we also identified the gene DSYB for dimethylsulphoniopropionate (DMSP) biosynthesis. Biosynthesis of this important stress-protectant and bacterial chemoattractant is typically found in photosynthetic eukaryotes and has not before been identified in heterotrophic stramenopiles. Together, our study reveals the metabolic attributes of a hitherto understudied organism, advancing knowledge of the evolution and adaptations of the stramenopiles and informing future culturing efforts.

microbiology↗

bioRxiv2022

A common human MLKL polymorphism confers resistance to negative regulation by phosphorylation

Across the globe, 2-3% of humans carry the p.Ser132Pro single nucleotide polymorphism in MLKL, the terminal effector protein of the inflammatory form of programmed cell death, necroptosis. We show that this substitution confers a gain in necroptotic function in human cells, with more rapid accumulation of activated MLKLS132P in biological membranes and MLKLS132P overriding pharmacological and endogenous inhibition of MLKL. In mouse cells, the equivalent Mlkl S131P mutation confers a gene dosage dependent reduction in sensitivity to TNF-induced necroptosis in both hematopoietic and non-hematopoietic cells, but enhanced sensitivity to IFN-{beta} induced death in non-hematopoietic cells. In vivo, MlklS131P homozygosity reduces the capacity to clear Salmonella from major organs and retards recovery of hematopoietic stem cells. Thus, by dysregulating necroptosis, the S131P substitution impairs the return to homeostasis after systemic challenge. Present day carriers of the MLKL S132P polymorphism may be the key to understanding how MLKL and necroptosis modulate the progression of complex polygenic human disease.

immunology↗

bioRxiv2021

Multi-omic Analysis of Developing Human Retina and Organoids Reveals Cell-Specific Cis-Regulatory Elements and Mechanisms of Non-Coding Genetic Disease Risk.

Cis-regulatory elements (CREs) play a critical role in the development, maintenance, and disease-states of all human cell types. In the human retina, CREs have been implicated in a variety of inherited retinal disorders. To characterize cell-class-specific CREs in the human retina and elucidate their potential functions in development and disease, we performed single-nucleus (sn)ATAC-seq and snRNA-seq on the developing and adult human retina and on human retinal organoids. These analyses allowed us to identify cell-class-specific CREs, enriched transcription factor binding motifs, putative target genes, and to examine how these features change over development. By comparing DNA accessibility between the human retina and retinal organoids we found that CREs in organoids are highly correlated at the single-cell level, validating the use of organoids as a model for studying disease-associated CREs. As a proof of concept, we studied the function of a disease-associated CRE at 5q14.3 in organoids, identifying its principal target gene as the miR-9-2 primary transcript and demonstrating a dual role for this CRE in regulating neurogenesis and gene regulatory programs in mature glia. This study provides a rich resource for characterizing cell-class-specific CREs in the human retina and showcases retinal organoids as a model in which to study the function of retinal CREs that influence retinal development and disease. HIGHLIGHTSO_LISingle-cell map of cis-regulatory elements in developing and adult human retina. C_LIO_LICorrelation of single-cell DNA accessibility between human retina and retinal organoids. C_LIO_LIAssociation of disease risk loci with cell-class-specific accessibility. C_LIO_LIModeling of enhancer function at the 5q14.3 retinal disease-risk locus. C_LI

developmental biology↗

bioRxiv2020

The guidance and adhesion protein FLRT2 dimerizes in cis via dual Small-X3-Small transmembrane motifs

Fibronectin Leucine-rich Repeat Transmembrane (FLRT 1-3) proteins are a family of broadly expressed single-spanning transmembrane receptors that play key roles in development. Their extracellular domains mediate homotypic cell-cell adhesion and heterotypic protein interactions with other receptors to regulate cell adhesion and guidance. These in trans FLRT interactions determine the formation of signaling complexes of varying complexity and function. Whether FLRTs also interact at the surface of the same cell, in cis, remains unknown. Here, molecular dynamics simulations reveal two dimerization motifs in the FLRT2 transmembrane helix. Single particle tracking experiments show that these Small-X3-Small motifs synergize with a third dimerization motif encoded in the extracellular domain to permit the cis association and co-diffusion patterns of FLRT2 receptors on cells. These results may point to a competitive switching mechanism between in cis and in trans interactions which suggests that homotypic FLRT interaction mirrors the functionalities of classic adhesion molecules. FieldsStructural Biology and Biophysics / Computational Biology

biophysics↗

bioRxiv2019

Nucleosome scaffolding by Brd4 tandem bromodomains in acetylation-dependent chromatin compartmentalization

Bromodomain binding of acetyl-lysine residues is a crucial step in many epigenetic mechanisms governing transcription. Nearly half of human bromodomains exist in tandem with at least one other bromodomain on a single protein. The Bromodomain and ExtraTerminal domain (BET) familyof proteins (BrdT, Brd2, Brd3 and Brd4) each encode two bromodomains at their N-termini and are important regulators of acetylation-dependent transcription in homeostasis and disease. Previous efforts have focused on identifying protein acetylation sites bound by individual bromodomains. However, the mechanisms through which tandem bromodomains act cooperatively on chromatin are largely unknown. Here, we first used small angle x-ray scattering combined with Rosetta ab initio modeling to explore conformational space available to BET tandem bromodomains. For Brd4, the flexible tandem bromodomain linker allows for distances between the two acetyl-lysine binding sites ranging from 15 to 157 [A]. Using a bioluminescence resonance energy transfer assay, we show a clear distance dependence for Brd4 tandem bromodomain bivalent binding of multiply acetylated histone H4 peptides. However, isothermal titration calorimetry studies revealed Brd4 binding affinity toward multiply acetylated peptides does not correlate with the potential for bivalent binding. We used sucrose gradient assays to provide direct evidence in vitro that Brd4 tandem bromodomains can simultaneously bind and scaffold multiple acetylated nucleosomes. Intriguingly, our bioinformatic analysis of deposited chromatin immunoprecipitation sequencing data indicates that Brd4 colocalizes with subsets of histone acetyl-lysine sites across transcriptionally active chromatin compartments. These findings support our hypothesis that scaffolding of acetylated nucleosomes by Brd4 tandem bromodomains contributes to higher-order chromatin architecture.

biochemistry↗