Biology subjects

Yoannidis, D.

Publications and source records attributed to Yoannidis, D..

3 recordsLinked to original sources

bioRxiv2025

macpie: scalable workflow for high-throughput transcriptomic profiling

High-throughput transcriptomic profiling (HTTr) enables scalable characterisation of transcriptional responses to chemical and genetic perturbations. While plate-based technologies such as MAC-Seq, TempO-seq and PLATE-seq have made HTTr more accessible, they pose unique computational challenges in modelling data and integration across modalities. We present macpie, an R package designed to streamline the analysis of HTTr data from plate-based screens. Built on the tidySeurat framework, macpie streamlines the entire analytical pipeline from preprocessing and quality control to pathway enrichment, chemical feature extraction, and multimodal data integration. The package incorporates multiple statistical frameworks and leverages parallelisation for scalability. By leveraging Docker and Nextflow, macpie ensures reproducibility and ease of use for transcriptome-wide screening. AvailabilityThe R package macpie is freely available at https://github.com/PMCC-BioinformaticsCore/macpie, with images of the working environment hosted at Docker Hub: xliu81/macpie. A companion Nextflow pipeline for preprocessing from FASTQ files is available at https://github.com/PMCC-BioinformaticsCore/dinoflow. Contactnenad.bartonicek@petermac.org Supplementary informationPackage vignettes with the full analytical workflow available at https://pmcc-bioinformaticscore.github.io/macpie/articles/macpie.html

bioinformatics↗

bioRxiv2025

Enhanced efficacy of a specific HDAC3 inhibitor in combination with 5-Azacitidine against diffuse large B-cell lymphoma

Diffuse large B-cell lymphoma (DLBCL) refers to an aggressive lymphoma that arises from germinal center (GC) B-cells, which differentiate into plasma cells (PC) to produce high affinity antibodies. 40% of DLBCL patients relapse or are refractory to the conventional immunochemotherapy treatment, usually with fatal consequences. Therefore, there is an unmet critical need to find more targeted therapies for DLBCL. DLBCL are characterized by profound alterations in the epigenome, which are correlated with poor survival. While epigenetic therapies are used as anti-cancer treatments, their full potential has not been achieved, mainly because of their limited efficacy when used as monotherapies and recurrent side effects associated with their low specificity. The abnormal epigenetic landscape of DLBCL tumors is associated with a blockade in GC exit and differentiation programs, which are regulated by the transcription factor BCL6. This aberrant repression of BCL6-target genes is mediated at least by two epigenetic mechanisms: 1) increased DNA methylation and 2) loss of acetylation of the lysine 27 of histone 3 (H3K27ac)-through recruitment of histone deacetylase 3 (HDAC3). Therefore, we investigated the efficacy against DLBCL of a novel combinatorial epigenetic therapy using the hypomethylating agent (HMA) 5-Azacitidine (5-Aza) and a specific HDAC3 inhibitor (HDAC3i). We found that treatment with 5-Aza and HDAC3i had a potent synergistic anti-tumor activity in vitro and in vivo, which was superior to the effect of each single drug or 5-Aza combined with non-specific HDACi and, importantly, was not associated with toxicity in normal cells. We also demonstrated that the combined 5-Aza and HDAC3i treatment induced the epigenetic remodeling of DLBCL cells, which resulted in a more potent re-expression of PC differentiation genes, including XBP1 and ATF4, compared to each drug used as single agents. Our results highlight the importance of targeting multiple layers of the epigenome to maximize the efficacy of epigenetic-based therapies.

cancer biology↗

bioRxiv2022

RNA decay defines the therapeutic response to transcriptional perturbation in cancer

Therapeutic targeting of dysregulated transcriptional programs has arisen as a promising strategy for the treatment of leukaemias. The therapeutic response to small molecule inhibitors of Bromodomain-Containing Proteins (BRD), such as BRD2 and BRD4, P300/cAMP-response element binding protein (CBP) and Cyclin Dependent Kinases (CDKs), is generally attributed to the selective disruption of oncogenic gene expression networks driven by enhancers, super-enhancers (SEs) and lineage-specific transcription factors (TFs), including the c-MYC oncogene. Using technologies such as thiol (SH)-linked alkylation for the metabolic sequencing of RNA sequencing (SLAM-seq) to profile messenger RNA (mRNA) decay and production rates, we demonstrate that gene intrinsic properties largely govern the selectivity associated with transcriptional inhibition, where total mRNA response signatures are dominated with genes that have short transcript half-lives, including those regulated by SEs and oncogenic TFs. Further highlighting that gene sensitivities only occur in the context of short transcript half-lives, stabilisation of the c-MYC transcript through changes in the 3 UTR rendered it insensitive to transcriptional targeting. However, this was not sufficient to rescue c-MYC target gene transcription and anti-leukaemia effects following transcriptional inhibition. Importantly, long-lived mRNAs encoding essential genes that evade transcriptional targeting can be rendered sensitive via modulation of mRNA decay kinetics through inhibition of the RNA Binding Protein (RBP), ELAV Like RNA binding protein 1 (ELAVL1)/ Human Antigen R (HuR). Taken together, these data demonstrate that mRNA decay shapes the therapeutic response to transcriptional perturbation and can be modulated for novel therapeutic outcomes using transcriptional agents in leukaemia.

cancer biology↗