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Nature Oct 2023Integrating human genomics and proteomics can help elucidate disease mechanisms, identify clinical biomarkers and discover drug targets. Because previous proteogenomic...
Integrating human genomics and proteomics can help elucidate disease mechanisms, identify clinical biomarkers and discover drug targets. Because previous proteogenomic studies have focused on common variation via genome-wide association studies, the contribution of rare variants to the plasma proteome remains largely unknown. Here we identify associations between rare protein-coding variants and 2,923 plasma protein abundances measured in 49,736 UK Biobank individuals. Our variant-level exome-wide association study identified 5,433 rare genotype-protein associations, of which 81% were undetected in a previous genome-wide association study of the same cohort. We then looked at aggregate signals using gene-level collapsing analysis, which revealed 1,962 gene-protein associations. Of the 691 gene-level signals from protein-truncating variants, 99.4% were associated with decreased protein levels. STAB1 and STAB2, encoding scavenger receptors involved in plasma protein clearance, emerged as pleiotropic loci, with 77 and 41 protein associations, respectively. We demonstrate the utility of our publicly accessible resource through several applications. These include detailing an allelic series in NLRC4, identifying potential biomarkers for a fatty liver disease-associated variant in HSD17B13 and bolstering phenome-wide association studies by integrating protein quantitative trait loci with protein-truncating variants in collapsing analyses. Finally, we uncover distinct proteomic consequences of clonal haematopoiesis (CH), including an association between TET2-CH and increased FLT3 levels. Our results highlight a considerable role for rare variation in plasma protein abundance and the value of proteogenomics in therapeutic discovery.
Topics: Humans; Alleles; Biological Specimen Banks; Biomarkers; Blood Proteins; Databases, Factual; Exome; Genetic Association Studies; Genomics; Hematopoiesis; Mutation; Plasma; Proteomics; United Kingdom
PubMed: 37794183
DOI: 10.1038/s41586-023-06547-x -
Gut Feb 2024Metastasis is the major cause of cancer death. However, what types of heterogenous cancer cells in primary tumour and how they metastasise to the target organs remain...
OBJECTIVE
Metastasis is the major cause of cancer death. However, what types of heterogenous cancer cells in primary tumour and how they metastasise to the target organs remain largely undiscovered.
DESIGN
We performed single-cell RNA sequencing and spatial transcriptomic analysis in primary colorectal cancer (CRC) and metastases in the liver (lCRC) or ovary (oCRC). We also conducted immunofluorescence staining and functional experiments to examine the mechanism.
RESULTS
Integrative analyses of epithelial cells reveal a stem-like cell cluster with high () and () expression as the metastatic culprit. This cell cluster comprising distinct subpopulations shows distinct liver or ovary metastatic preference. Population 1 (P1) cells with high and expression are enriched in primary CRC and oCRC, thus may be associated with ovarian metastasis. P3 cells having a similar expression pattern as cholangiocytes are found mainly in primary CRC and lCRC, presuming to be likely the culprits that specifically metastasise to the liver. Stem-like cells interacted with cancer-associated fibroblasts and endothelial cells via the DLL4-NOTCH signalling pathway to metastasise from primary CRC to the ovary. In the oCRC microenvironment, myofibroblasts provide cancer cells with glutamine and perform a metabolic reprogramming, which may be essential for cancer cells to localise and develop in the ovary.
CONCLUSION
We uncover a mechanism for organ-specific CRC metastasis.
Topics: Female; Humans; Colorectal Neoplasms; Endothelial Cells; Liver Neoplasms; Gene Expression Profiling; Signal Transduction; Gene Expression Regulation, Neoplastic; Neoplasm Metastasis; Tumor Microenvironment; Basic Helix-Loop-Helix Transcription Factors
PubMed: 38050068
DOI: 10.1136/gutjnl-2023-330243 -
Nature Communications Jul 2023Skeletal muscle fibers express distinct gene programs during development and maturation, but the underlying gene regulatory networks that confer stage-specific myofiber...
Skeletal muscle fibers express distinct gene programs during development and maturation, but the underlying gene regulatory networks that confer stage-specific myofiber properties remain unknown. To decipher these distinctive gene programs and how they respond to neural activity, we generated a combined multi-omic single-nucleus RNA-seq and ATAC-seq atlas of mouse skeletal muscle development at multiple stages of embryonic, fetal, and postnatal life. We found that Myogenin, Klf5, and Tead4 form a transcriptional complex that synergistically activates the expression of muscle genes in developing myofibers. During myofiber maturation, the transcription factor Maf acts as a transcriptional switch to activate the mature fast muscle gene program. In skeletal muscles of mutant mice lacking voltage-gated L-type Ca channels (Cav1.1), Maf expression and myofiber maturation are impaired. These findings provide a transcriptional atlas of muscle development and reveal genetic links between myofiber formation, maturation, and contraction.
Topics: Mice; Animals; Muscle Fibers, Skeletal; Muscle, Skeletal; Gene Expression Regulation; Transcription Factors; Cell Differentiation
PubMed: 37468485
DOI: 10.1038/s41467-023-40073-8 -
Nature Communications Jun 2023Altered protein phosphorylation in cancer cells often leads to surface presentation of phosphopeptide neoantigens. However, their role in cancer immunogenicity remains...
Altered protein phosphorylation in cancer cells often leads to surface presentation of phosphopeptide neoantigens. However, their role in cancer immunogenicity remains unclear. Here we describe a mechanism by which an HLA-B*0702-specific acute myeloid leukemia phosphoneoantigen, pMLL (EPR(pS)PSHSM), is recognized by a cognate T cell receptor named TCR27, a candidate for cancer immunotherapy. We show that the replacement of phosphoserine P with serine or phosphomimetics does not affect pMHC conformation or peptide-MHC affinity but abrogates TCR27-dependent T cell activation and weakens binding between TCR27 and pMHC. Here we describe the crystal structures for TCR27 and cognate pMHC, map of the interface produced by nuclear magnetic resonance, and a ternary complex generated using information-driven protein docking. Our data show that non-covalent interactions between the epitope phosphate group and TCR27 are crucial for TCR specificity. This study supports development of new treatment options for cancer patients through target expansion and TCR optimization.
Topics: Humans; Phosphopeptides; Receptors, Antigen, T-Cell; Protein Binding
PubMed: 37353482
DOI: 10.1038/s41467-023-39425-1 -
Frontiers in Immunology 2023Activator protein-1 (AP-1) is a transcription factor that consists of a diverse group of members including Jun, Fos, Maf, and ATF. AP-1 involves a number of processes... (Review)
Review
Activator protein-1 (AP-1) is a transcription factor that consists of a diverse group of members including Jun, Fos, Maf, and ATF. AP-1 involves a number of processes such as proliferation, migration, and invasion in cells. Dysfunctional AP-1 activity is associated with cancer initiation, development, invasion, migration and drug resistance. Therefore, AP-1 is a potential target for cancer targeted therapy. Currently, some small molecule inhibitors targeting AP-1 have been developed and tested, showing some anticancer effects. However, AP-1 is complex and diverse in its structure and function, and different dimers may play different roles in different type of cancers. Therefore, more research is needed to reveal the specific mechanisms of AP-1 in cancer, and how to select appropriate inhibitors and treatment strategies. Ultimately, this review summarizes the potential of combination therapy for cancer.
Topics: Humans; Transcription Factor AP-1; Proto-Oncogene Proteins c-fos; Proto-Oncogene Proteins c-jun; Gene Expression Regulation; Neoplasms
PubMed: 37483616
DOI: 10.3389/fimmu.2023.1224892 -
Nature Cell Biology Dec 2023MAF amplification increases the risk of breast cancer (BCa) metastasis through mechanisms that are still poorly understood yet have important clinical implications....
MAF amplification increases the risk of breast cancer (BCa) metastasis through mechanisms that are still poorly understood yet have important clinical implications. Oestrogen-receptor-positive (ER) BCa requires oestrogen for both growth and metastasis, albeit by ill-known mechanisms. Here we integrate proteomics, transcriptomics, epigenomics, chromatin accessibility and functional assays from human and syngeneic mouse BCa models to show that MAF directly interacts with oestrogen receptor alpha (ERα), thereby promoting a unique chromatin landscape that favours metastatic spread. We identify metastasis-promoting genes that are de novo licensed following oestrogen exposure in a MAF-dependent manner. The histone demethylase KDM1A is key to the epigenomic remodelling that facilitates the expression of the pro-metastatic MAF/oestrogen-driven gene expression program, and loss of KDM1A activity prevents this metastasis. We have thus determined that the molecular basis underlying MAF/oestrogen-mediated metastasis requires genetic, epigenetic and hormone signals from the systemic environment, which influence the ability of BCa cells to metastasize.
Topics: Animals; Female; Humans; Mice; Breast Neoplasms; Cell Line, Tumor; Chromatin; Epigenesis, Genetic; Estrogen Receptor alpha; Estrogens; Histone Demethylases; Gene Amplification; Proto-Oncogene Proteins c-maf
PubMed: 37945904
DOI: 10.1038/s41556-023-01281-y -
European Journal of Medical Research Nov 2023Long noncoding RNAs (lncRNAs) refer to a type of non-protein-coding transcript of more than 200 nucleotides. LncRNAs play fundamental roles in disease development and... (Review)
Review
Long noncoding RNAs (lncRNAs) refer to a type of non-protein-coding transcript of more than 200 nucleotides. LncRNAs play fundamental roles in disease development and progression, and lncRNAs are dysregulated in many pathophysiological processes. Thus, lncRNAs may have potential value in clinical applications. The lncRNA, MAF BZIP Transcription Factor G (MAFG)-AS1, is dysregulated in several cancer, including breast cancer, lung cancer, liver cancer, bladder cancer, colorectal cancer, gastric cancer, esophagus cancer, prostate cancer, pancreatic cancer, ovarian cancer, and glioma. Altered MAFG-AS1 levels are also associated with diverse clinical characteristics and patient outcomes. Mechanistically, MAFG-AS1 mediates a variety of cellular processes via the regulation of target gene expression. Therefore, the diagnostic, prognostic, and therapeutic aspects of MAFG-AS1 have been widely explored. In this review, we discuss the expression, major roles, and molecular mechanisms of MAFG-AS1, the relationship between MAFG-AS1 and clinical features of diseases, and the clinical applications of MAFG-AS1.
Topics: Male; Humans; RNA, Long Noncoding; MicroRNAs; Lung Neoplasms; Breast Neoplasms; Prognosis; Gene Expression Regulation, Neoplastic; Cell Proliferation; Cell Line, Tumor; Repressor Proteins; MafG Transcription Factor
PubMed: 37941063
DOI: 10.1186/s40001-023-01486-9 -
Wellcome Open Research 2023CD4 Th1 cells producing IFN-γ are required to eradicate intracellular pathogens, however if uncontrolled these cells can cause immunopathology. The cytokine IL-10 is...
BACKGROUND
CD4 Th1 cells producing IFN-γ are required to eradicate intracellular pathogens, however if uncontrolled these cells can cause immunopathology. The cytokine IL-10 is produced by multiple immune cells including Th1 cells during infection and regulates the immune response to minimise collateral host damage. In this study we aimed to elucidate the transcriptional network of genes controlling the expression of and proinflammatory cytokines, including in Th1 cells differentiated from mouse naive CD4 T cells.
METHODS
We applied computational analysis of gene regulation derived from temporal profiling of gene expression clusters obtained from bulk RNA sequencing (RNA-seq) of flow cytometry sorted naïve CD4 T cells from mouse spleens differentiated into Th1 effector cells with IL-12 and IL-27 to produce and compared to IL-27 alone which express only or IL-12 alone which express and no or medium control driven-CD4 T cells which do not express effector cytokines Data were integrated with analysis of active genomic regions from these T cells using an assay for transposase-accessible chromatin with sequencing (ATAC)-seq, integrated with literature derived-Chromatin-immunoprecipitation (ChIP)-seq data and the RNA-seq data, to elucidate the transcriptional network of genes controlling expression of and pro-inflammatory effector genes in Th1 cells. The co-dominant role for the transcription factors, (encoding Blimp-1) and (encoding c-Maf) in cytokine gene regulation in Th1 cells, was confirmed using T cells obtained from mice with T-cell specific deletion of these transcription factors.
RESULTS
We show that the transcription factors Blimp-1 and c-Maf each have unique and common effects on cytokine gene regulation and not only co-operate to induce gene expression in IL-12 plus IL-27 differentiated mouse Th1 cells, but additionally directly negatively regulate key proinflammatory cytokines including , thus providing mechanisms for reinforcement of regulated Th1 cell responses.
CONCLUSIONS
These data show that Blimp-1 and c-Maf positively and negatively regulate a network of both unique and common anti-inflammatory and pro-inflammatory genes to reinforce a Th1 response in mice that will eradicate pathogens with minimum immunopathology.
PubMed: 38074197
DOI: 10.12688/wellcomeopenres.19680.2 -
Blood Advances Nov 2023Deregulated expression of lineage-affiliated transcription factors (TFs) is a major mechanism of oncogenesis. However, how the deregulation of nonlineage affiliated TF...
Deregulated expression of lineage-affiliated transcription factors (TFs) is a major mechanism of oncogenesis. However, how the deregulation of nonlineage affiliated TF affects chromatin to initiate oncogenic transcriptional programs is not well-known. To address this, we studied the chromatin effects imposed by oncogenic MAF as the cancer-initiating driver in the plasma cell cancer multiple myeloma. We found that the ectopically expressed MAF endows myeloma plasma cells with migratory and proliferative transcriptional potential. This potential is regulated by the activation of enhancers and superenhancers, previously inactive in healthy B cells and plasma cells, and the cooperation of MAF with the plasma cell-defining TF IRF4. Forced ectopic MAF expression confirms the de novo ability of oncogenic MAF to convert transcriptionally inert chromatin to active chromatin with the features of superenhancers, leading to the activation of the MAF-specific oncogenic transcriptome and the acquisition of cancer-related cellular phenotypes such as CCR1-dependent cell migration. These findings establish oncogenic MAF as a pioneer transcription factor that can initiate as well as sustain oncogenic transcriptomes and cancer phenotypes. However, despite its pioneer function, myeloma cells remain MAF-dependent, thus validating oncogenic MAF as a therapeutic target that would be able to circumvent the challenges of subsequent genetic diversification driving disease relapse and drug resistance.
Topics: Humans; Multiple Myeloma; Gene Expression Regulation; Plasma Cells; B-Lymphocytes; Chromatin
PubMed: 37224458
DOI: 10.1182/bloodadvances.2023009772 -
Genes Sep 2023Large musculoaponeurotic fibrosarcoma (MAF) transcription factors contain acidic, basic, and leucine zipper regions. Four types of MAF have been elucidated in mice and... (Review)
Review
Large musculoaponeurotic fibrosarcoma (MAF) transcription factors contain acidic, basic, and leucine zipper regions. Four types of MAF have been elucidated in mice and humans, namely c-MAF, MAFA, MAFB, and NRL. This review aimed to elaborate on the functions of MAF transcription factors that have been studied in vivo so far, as well as describe the pathology of human patients and corresponding mouse models with c-MAF, MAFA, and MAFB point mutations. To identify the functions of MAF transcription factors in vivo, we generated genetically modified mice lacking c-MAF, MAFA, and MAFB and analyzed their phenotypes. Further, in recent years, c-MAF, MAFA, and MAFB have been identified as causative genes underpinning many rare diseases. Careful observation of human patients and animal models is important to examine the pathophysiological mechanisms underlying these conditions for targeted therapies. Murine models exhibit phenotypes similar to those of human patients with c-MAF, MAFA, and MAFB mutations. Therefore, generating these animal models emphasizes their usefulness for research uncovering the pathophysiology of point mutations in MAF transcription factors and the development of etiology-based therapies.
Topics: Humans; Mice; Animals; Transcription Factors; Maf Transcription Factors, Large; MafB Transcription Factor; Insulin; Point Mutation
PubMed: 37895232
DOI: 10.3390/genes14101883