Project description:Aging is a time-dependent biological phenomenon governed by complex networks of regulatory components and their transitions over lifetime. Yet, there have been limited efforts to pin down age-associated networks and map their dynamic characteristics onto aging phenotypes. Here, we built time-course genetic regulatory networks of NAM/ATAF/CUC (NAC) transcription factors during the course of leaf aging in Arabidopsis, using causal regulatory relationships among NACs identified from mutants of 49 aging-associated NACs. These temporal networks revealed a regulatory inversion from activating to repressive regulatory modes at a pre-senescent stage. The inversion was governed by three hub NACs, and their mutants conferred earlier aging with altered expression of reactive oxygen species and salicylic acid response genes. Overexpression of the hub NACs delayed the regulatory inversion, rendering delayed age-dependent cell death. We conclude that the regulatory inversion in NAC networks at a pre-senescent stage directs when age-dependent cell death should proceed in plants.
Project description:Aging is a time-dependent biological phenomenon governed by complex networks of regulatory components and their transitions over lifetime. Yet, there have been limited efforts to pin down age-associated networks and map their dynamic characteristics onto aging phenotypes. Here, we built time-course genetic regulatory networks of NAM/ATAF/CUC (NAC) transcription factors during the course of leaf aging in Arabidopsis, using causal regulatory relationships among NACs identified from mutants of 49 aging-associated NACs. These temporal networks revealed a regulatory inversion from activating to repressive regulatory modes at a pre-senescent stage. The inversion was governed by three hub NACs, and their mutants conferred earlier aging with altered expression of reactive oxygen species and salicylic acid response genes. Overexpression of the hub NACs delayed the regulatory inversion, rendering delayed age-dependent cell death. We conclude that the regulatory inversion in NAC networks at a pre-senescent stage directs when age-dependent cell death should proceed in plants.
Project description:To understand how the NAC transcription factor KIL1 regulates age-induced senescence and cell death in maize silks, we need to get a genome-wide view on its downstream targets. We propose to compare the transcriptome profiles of GOF and LOF transgenic silk tissue with the profile of wild-type B104 silk. 1 cm of basal part of silk from rings 6-10 from plants harboring the dominant-negative repressor proSILK1:KIL1-SRDX, proSILK1:KIL1 overexpressing line, and wild type B104 will be harvested at 11 DASE. This will allow to compare and contrast the expression profiles of KIL1 LOF and GOF mutants with transcriptome data derived from wild type senescent silk.
Project description:The NanoString analysis of 770 genes expressed by 24 immune cell types in the tumors at 10 days after injection were performed. The Nanostring analysis uncovered marked difference in key immune regulatory networks associated with T, DC, NC and macrophage function
Project description:The NanoString analysis of 784 genes expressed by 24 immune cell types in the melanoma cell at 11 days after injection were performed. The Nanostring analysis uncovered marked difference in key immune regulatory networks associated with T, DC, NC and macrophage function
Project description:We evaluated if a higher plane of maternal nutrition during late gestation and weaning age alters the offspring’s Longissimus muscle (LM) transcriptome. A microarray analysis was performed in LM samples of early (EW) and normal weaned (NW) Angus × Simmental calves born from cows that were grazing endophyte-infected tall fescue/red clover pastures with no supplement (low plane of nutrition (LPN)), or supplemented with 2.3 kg of dried distiller’s grains with solubles and soyhulls (70% DDGS/30% soyhulls) (medium plane of nutrition (MPN)) during the last 90 days of gestation. Biopsies were harvested at 78, 187 and 354 days of age. Bioinformatics analysis highlighted that offspring transcriptome did not respond markedly to cow plane of nutrition, resulting in only 13 differentially expressed genes. However, weaning age and a high-starch diet strongly impacted the transcriptome, especially the immediate activation of the lipogenic program in EW steers. In addition, between 78 and 187 days of age, these animals had an activation of the innate immune system due presumably to macrophage infiltration in intramuscular fat. Between 187 and 354 days of age (i.e. the fattening phase), NW steers had an activation of the lipogenic transcriptome machinery, while EW steers had a clear gene transcription inhibition. The latter appears to have occurred through the epigenetic control of histone acetylases, which were down-regulated. Higher cow plane of nutrition alone affected 35 genes in the LM of steers that underscore the presence of a mechanism of macrophage infiltration likely originating from localized oxidative stress as a result of increased levels of hypoplasia and hypertrophy in LM.
Project description:Neoadjuvant chemotherapy (NAC) is a critical component of breast cancer treatment, but the molecular mechanisms underlying resistance remain poorly understood. This study aimed to identify transcriptomic changes associated with NAC resistance across four breast cancer subtypes: Luminal A, Luminal B/HER2-positive, Luminal B/HER2-negative, and Triple-Negative Breast Cancer (TNBC). RNA-seq analysis was performed on paired pre- and post-NAC breast cancer samples from 35 non-responders. Differentially expressed genes (DEGs) were identified, and functional enrichment analyses were conducted. Protein-protein interaction (PPI) networks were constructed to identify hub genes. Tumor microenvironment (TME) infiltration was estimated using deconvolution algorithms. The results revealed distinct gene expression profiles between pre- and post-NAC samples, with FOS and NR4A1 being common DEGs across all subtypes. Enriched pathways varied among subtypes, including signal transduction, estrogen biosynthesis, extracellular matrix organization, dendritic cell activation, and B cell activation. TME analysis showed increased infiltration of specific immune cell populations after NAC, including CD4 memory T cells, regulatory T cells, neutrophils, macrophages, and mast cells, varying by subtype. These findings suggest that NAC modulates gene expression, cellular activity, and TME interactions, potentially contributing to treatment resistance. Understanding the molecular determinants of NAC resistance is crucial for developing targeted therapeutic strategies and improving outcomes for breast cancer patients.