Biology subjects

Chu, Y.-H.

Publications and source records attributed to Chu, Y.-H..

3 recordsLinked to original sources

bioRxiv2024

Prioritizing Metabolic Gene Regulators through Multi-Omic Network Integration in Maize

Gene regulatory networks (GRNs) link transcription factors (TFs) to the biological processes they control. Assembling them remains difficult because the relevant data types (gene expression, protein-DNA interactions, and genetic variation) are large, heterogeneous, and rarely combined. Here, we developed and benchmarked a framework that integrates these data into TF-function predictions in maize. We assembled four complementary TF-target gene network layers, based on expression, protein-DNA interaction, trans-expression quantitative trait loci (eQTL), and cis-eQTL-supported interaction, from 46 Random Forest (RF)-inferred regulatory networks, 283 protein-DNA interaction assays, and eQTLs derived from 16 million SNPs across 304 inbred lines. Together these layers comprised ~4.6 million interactions. We then compared three strategies for integrating them, benchmarking each against published TF knockout data. A network-based approach, which represents every gene as a low-dimensional vector (embedding) learned from the combined network, outperformed the two overlap-based strategies, annotating over eight times more TFs (~3,000), agreeing most closely with gene knockout responses where predictions existed, and remaining robust when individual layers lacked data. The predictions recovered TF functions and predicted new regulators of hormone, developmental, and metabolic processes, which we prioritized per process and mapped to specific conditions. Using similarity on the low-dimensional vector representation (embedding), we further identified candidate functionally redundant or diverged TF paralogs. Because it relies only on data types now common across species, the framework provides a generalizable template for prioritizing regulatory genes in maize and other plants.

plant biology↗

bioRxiv2023

Hydrogen Sulfide Coordinates Glucose Metabolism Switch through Destabilizing Tetrameric Pyruvate Kinase M2

Cancer cells reprogram their glucose metabolic pathway from oxidative phosphorylation toward aerobic glycolysis. Pyruvate kinase M2 (PKM2), which converts phosphoenolpyruvate (PEP) to pyruvate, is considered the rate-limiting enzyme involved in cancer glucose metabolism. By reducing PKM2 enzyme activity, cancer cells attain a greater fraction of glycolytic metabolites for macromolecule synthesis needed for rapid proliferation. Here we demonstrate that hydrogen sulfide (H2S) destabilizes PKM2 tetramer into dimer/monomer, leading to reduced PKM2 enzyme activity and an increase in the activation of nuclear transcriptional genes mediated by dimeric PKM2. Proteomic profiling of endogenous PKM2 reveals the occurrence of sulfhydration at cysteines, notably at cysteine 326. Blocking PKM2 sulfhydration at cysteine 326 through amino acid mutation stabilizes PKM2 tetramer and crystal structure further indicating that the tetramer organization of PKM2C326S is different from the currently known T or R states, revealing PKM2C326S as a newly identified form. The presence of a PKM2C326S mutant in cancer cells effectively rewires glucose metabolism to mitochondrial respiration, resulting in the significant inhibition of tumor growth. Collectively, PKM2 sulfhydration by H2S serves as a glucose metabolic rewiring mechanism in promoting tumorigenesis, and inhibition of PKM2 sulfhydration may be applied as a new therapeutic approach targeting cancer metabolism. One-Sentence SummaryH2S rewires glucose metabolism by destabilizing PKM2 tetramerization majorly through sulfhydration at cysteine 326 HighlightsO_LIH2S enhances PKM2 dissociation from tetramer to dimer to facilitate dimeric PKM2 nuclear translocation. C_LIO_LIH2S modifies PKM2 sulfhydration, notably at cysteine 326. C_LIO_LIThe crystal structure reveals PKM2C326S as a unique tetramer conformation. C_LIO_LIBlockage of PKM2 sulfhydration at C326 rewires cancer glucose metabolism and significantly inhibits tumor growth. C_LI

cancer biology↗

bioRxiv2023

Mutator transposon insertions within maize genes often provide a novel outward reading promoter

The highly active family of Mutator (Mu) DNA transposons has been widely used for forward and reverse genetics in maize. There are examples of Mu-suppressible alleles which result in conditional phenotypic effects based on the activity of Mu. Phenotypes from these Mu- suppressible mutations are observed in Mu-active genetic backgrounds, but absent when Mu activity is lost. For some Mu-suppressible alleles, phenotypic suppression likely results from an outward-reading promoter within Mu that is only active when the autonomous Mu element is silenced or lost. We isolated 35 Mu alleles from the UniformMu population that represent insertions in 24 different genes. Most of these mutant alleles are due to insertions within gene coding sequences, but several 5 UTR and intron insertions were included. RNA-seq and de novo transcript assembly were utilized to document the transcripts produced from 33 of these Mu insertion alleles. For 20 of the 33 alleles, there was evidence of transcripts initiating within the Mu sequence reading through the gene. This outward-reading promoter activity was detected in multiple types of Mu elements and doesnt depend on the orientation of Mu. Expression analyses of Mu-initiated transcripts revealed the Mu promoter often provides gene expression levels and patterns that are similar to the wild-type gene. These results suggest the Mu promoter may represent a minimal promoter that can respond to gene cis-regulatory elements. Findings from this study have implications for maize researchers using the UniformMu population, and more broadly highlights a strategy for transposons to co-exist with their host. Article SummaryMutator (Mu) transposable elements are a widely used tool for insertional mutagenesis in maize and often insert in the 5 regions of genes. The characterization of transcripts for Mu insertion alleles reveals complex transcripts. These often result in one transcript that covers the first portion of the gene terminating in Mu and a second transcript initiating within Mu covering the latter portion of the gene. This may reflect a strategy for Mu to minimize the consequences of insertions within genes.

plant biology↗