4052 results for "*geneti*"

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• From stem cells to somites: revealing genetic and exogenous factors of human embryogenesis

  Stem cell-based human embryo models offer an ethically tractable platform for studying early human development. This study employs somitoids, three-dimensional models of human somitogenesis, to investigate how transcriptional programs and culture conditions influence somite formation and segmentation. Pre-differentiation conditions strongly impact developmental potential, with StemFit medium outperforming mTeSR Plus in generating robust somite-like structures, despite minimal differences in transcriptomic and proteomic profiles. RNA-seq was performed on iPSCs cultured in mTeSR Plus or StemFit medium, as well as on day 5 somitoids derived from these conditions. Additional RNA-seq analyses included wildtype, BPTF, RBPJ, and CITED2 knockout lines, and CITED2 rescue lines. These targets were selected based on p300 proximity labeling to functionally validate identified p300 proximity interactors. To confirm that the p300–miniTurbo fusion remained functional, ChIP-seq was performed on undifferentiated iPSCs cultured in mTeSR Plus medium. Together, our findings highlight somitoids as a robust and scalable system for studying gene regulation during early human development, enabling functional interrogation of key chromatin-associated regulators driving somitogenesis.

  Study EGAS50000001900

• A targetable dependency on nonsense-mediated decay for cellular homeostasis and immune control in small cell lung cancer

  Small cell lung cancer (SCLC) is one of the most aggressive malignancies, characterized by rapid metastatic dissemination and poor overall survival. Despite harboring one of the highest tumor mutational burden (TMB), expectedly resulting in immunogenic neoantigens, patients with SCLC remain largely refractory to immunotherapy. We found abundant frameshift mutations in SCLC, regarded as highly immunogenic, counterbalanced by a hyperactive nonsense-mediated decay (NMD) pathway, responsible for frameshift-mRNA degradation. NMD activity correlated with tumor mutational burden (TMB) across cancers, suggesting that SCLC and other TMB-high cancers may depend on NMD to limit the accumulation of mutation-derived byproducts in order to maintain cellular homeostasis and evade immune recognition. In TMB-high SCLC models, inhibition of NMD impaired cell proliferation and induced ER stress-dependent apoptosis due to the accumulation of misfolded proteins. Genetic and pharmacological NMD inhibition in vivo effectively controlled TMB-high tumor growth without overt toxicity. By integrating genome and transcriptome sequencing with MHC-I immunopeptidomics and functional in vitro and in vivo assays, we identified that NMD inhibition boosted neoantigen expression and presentation by tumor cells and increased T cell recognition, thus enhancing overall tumor immunogenicity and further improving immunotherapy efficacy in vivo. Our work shows that SCLC – as a TMB-high cancer – relies on NMD for survival and immune escape, uncovering a novel TMB-dependent tractable vulnerability for this devastating disease.

  Study EGAS50000002061

• Single-Cell DNA Methylation Phylogeny Uncovers Alternative Epigenetic Pathways for MDS Transformation to AML

  This project investigates the transformation of myelodysplastic syndrome (MDS) to secondary acute myeloid leukemia (sAML), particularly after hypomethylating agent (HMA) therapy, a process linked to therapy resistance and poor survival using single-cell DNA methylation data together with sc-DNA, sc-Prot and sc-RNA data.The findings reveal novel epigenetic drivers of therapy resistance and sAML.

  Study EGAS50000001207

• A single-cell multi-omic atlas of the human pancreas reveals latent plasticity across development, health, and disease

  The pancreas plays a central role in major human diseases, yet our understanding of its cellular diversity and plasticity remains incomplete. Here, we present a single-cell multiomics atlas of the human pancreas, profiling over four million cells and nuclei from 57 donors across fetal development, adult homeostasis, and type 2 diabetes (T2D). Integrating sc/snRNA-seq, snATAC-seq, VASA-seq, spatial transcriptomics (Xenium), and multiplexed proteomics (CODEX), we resolve gene expression, chromatin accessibility, and spatial organization at high resolution. We identify transcriptionally plastic centroacinar-like cells (pCACs) in adults with fetal-like features, delineate endocrine and exocrine lineage trajectories during development, and uncover HNF1A-defined beta cell epigenetic states. In T2D, we observe shifts in beta cell subtypes and altered regulatory programs. Glucose perturbation of healthy islets reveals cell-type-specific adaptation and stress responses. This atlas provides a foundational framework to understand pancreas biology and the role of cellular plasticity in regeneration and disease.

  Study EGAS50000001872

• Investigating Host Genetic Risk Factors for Tuberculosis in Highly Endemic South African Populations

  It is apparent from our recent population genetic and admixture mapping work 1–3 that a substantial part of the ancestral input into the South African Coloured (SAC) population is from the San or Khoe groups, which are not well represented in publicly available genetic databases. It is a reasonable assumption that the SAC population in the Western Cape may have derived more genetic input from the present KhoeSan population in the Northern Cape than the San residing in Namibia. It was concluded by our group that it is indeed the southern African KhoeSan group, the ≠Khomani, that best represent the KhoeSan contribution seen in the SAC 4. More recently, it has been shown that there are ancestry related increases in TB susceptibility, especially with increased Bantu-speaking African and KhoeSan ancestry 5. We aim to elucidate the epidemiological and human-host genetic risk factors for TB and the immunological pathways modulating TB infection. The proposed sub-study will enroll people evaluated for TB at Northern Cape community health clinics and their contacts from their households and/or community. We will conduct a demographic interview, collect saliva, which will be used for genetic analysis, and blood to determine latent TB infection status and capture immunological responses to mycobacterial infections at the cellular level and RNA sequencing.

  Study EGAS00001007850

• Genetic control of naive T cell receptor gene usage in celiac disease

  We have characterized the TCR repertoire of naïve CD4+ T cells in 103 individuals with CeD and 103 control subjects by undertaking gene usage quantitative trait loci analyses based on repertoire sequencing and single nucleotide polymorphism genotyping. Variants within the TCR alpha and beta loci and HLA region as well as HLA-DQ allotypes and alleles were tested for association with TCR gene usage.

  Study EGAS50000001882

• Genetic control of naive B cell receptor gene usage in celiac disease

  We have characterized the BCR repertoire of naïve B cells in 102 individuals with CeD and 102 control subjects by undertaking gene usage quantitative trait loci analyses based on BCR repertoire sequencing and single nucleotide polymorphism genotyping within the IGH, IGK and IGL loci.

  Study EGAS50000001881

• Whole-Exome Sequencing of Tumor Biopsies from a Colorectal Cancer Patient with Two Distinct Primary Tumors and Matched Metastases

  Colorectal cancer (CRC) is a heterogeneous disease in which rare genetic alterations, such as neurotrophic receptor tyrosine kinase (NTRK) fusions, have emerged as clinically relevant therapeutic targets. Here, we report the case of a 69-year-old man with an advanced colorectal carcinoma comprising two intermixed but histologically distinct components: a predominant (>90%) poorly differentiated solid carcinoma and a conventional adenocarcinoma with mucinous features. Whole-exome sequencing (WES) of microdissected tumor regions (two primary tumors and two matched metastases) along with germline DNA analysis revealed profound genetic divergence between the two tumor components. This case illustrates the coexistence of two genetically independent yet spatially inseparable CRCs following distinct evolutionary trajectories—one driven by an NTRK1 fusion and microsatellite instability (MSI), and the other by canonical KRAS and SMAD4 alterations.

  Study EGAS50000001385

• CSF PBAT methylome profiling in multiple sclerosis - shallow seq

  This study contains shallow-depth post-bisulfite adaptor tagging (PBAT) whole-genome bisulfite sequencing data generated from cerebrospinal fluid (CSF) cells from individuals with relapsing-remitting multiple sclerosis and neurological disease controls. The shallow-sequencing dataset includes lower-depth technical replicate sequencing of discovery-cohort samples and an independent validation cohort. These data were generated to assess the reproducibility of candidate MS-associated DNA methylation differences identified by deep PBAT-seq and to support validation of methylation signatures in CSF immune cells. The study contributes to the characterization of immune regulatory, adhesion, migration and protocadherin-associated epigenetic changes in multiple sclerosis.

  Study EGAS50000001940

• mRNA-seq of paired Follicular Lymphoma (FL) patient samples before and after high-grade transformation to DLBCL (FL vs. tFL) from FFPE tissues

  The aim of this study was to analyze transcriptional changes in paired samples of follicular lymphoma (FL) and its histological transformation (tFL). Transformation of FL is an adverse event in the course of the disease and is associated with poor outcome. Several genetic aberrations have been linked to tFL pathogenesis, but gene expression changes and microenvironmental interactions have not been well characterized. We performed RNA profiling of FL and paired tFL samples transformed to DLBCL (n=11 pairs). For RNA profiling, we utilized libraries prepared using RNA isolated from archival FFPE tissues.

  Study EGAS50000000941