SAMD1 suppresses epithelial-mesenchymal transition pathways in pancreatic ductal adenocarcinoma.

Pancreatic ductal adenocarcinoma (PDAC) poses a significant threat due to its tendency to evade early detection, frequent metastasis, and the subsequent challenges in devising effective treatments. Processes that govern epithelial-mesenchymal transition (EMT) in PDAC hold promise for advancing novel therapeutic strategies. SAMD1 (SAM domain-containing protein 1) is a CpG island-binding protein that plays a pivotal role in the repression of its target genes.

IRF2BP2 counteracts the ATF7/JDP2 AP-1 heterodimer to prevent inflammatory overactivation in acute myeloid leukemia (AML) cells.

Acute myeloid leukemia (AML) is a hematological malignancy characterized by abnormal proliferation and accumulation of immature myeloid cells in the bone marrow. Inflammation plays a crucial role in AML progression, but excessive activation of cell-intrinsic inflammatory pathways can also trigger cell death. IRF2BP2 is a chromatin regulator implicated in AML pathogenesis, although its precise role in this disease is not fully understood.

Peptide-mediated inhibition of the transcriptional regulator Elongin BC induces apoptosis in cancer cells.

Inhibition of protein-protein interactions (PPIs) via designed peptides is an effective strategy to perturb their biological functions. The Elongin BC heterodimer (ELOB/C) binds to a BC-box motif and is essential for cancer cell growth. Here, we report a peptide that mimics the high-affinity BC-box of the PRC2-associated protein EPOP.

Polycomb-like Proteins in Gene Regulation and Cancer.

Polycomb-like proteins (PCLs) are a crucial group of proteins associated with the Polycomb repressive complex 2 (PRC2) and are responsible for setting up the PRC2.1 subcomplex. In the vertebrate system, three homologous PCLs exist: PHF1 (PCL1), MTF2 (PCL2), and PHF19 (PCL3).

Investigation of SAMD1 ablation in mice.

SAM domain-containing protein 1 (SAMD1) has been implicated in atherosclerosis, as well as in chromatin and transcriptional regulation, suggesting a versatile and complex biological function. However, its role at an organismal level is currently unknown. Here, we generated SAMD1 and SAMD1 mice to explore the role of SAMD1 during mouse embryogenesis.

IL-17A-producing CD8 T cells promote PDAC via induction of inflammatory cancer-associated fibroblasts.

Objective: Pancreatic ductal adenocarcinoma (PDAC) is characterised by an abundant desmoplastic stroma composed of cancer-associated fibroblasts (CAF) and interspersed immune cells. A non-canonical CD8 T-cell subpopulation producing IL-17A (Tc17) promotes autoimmunity and has been identified in tumours. Here, we evaluated the Tc17 role in PDAC.

The histone acetyltransferase KAT6A is recruited to unmethylated CpG islands via a DNA binding winged helix domain.

The lysine acetyltransferase KAT6A (MOZ, MYST3) belongs to the MYST family of chromatin regulators, facilitating histone acetylation. Dysregulation of KAT6A has been implicated in developmental syndromes and the onset of acute myeloid leukemia (AML). Previous work suggests that KAT6A is recruited to its genomic targets by a combinatorial function of histone binding PHD fingers, transcription factors and chromatin binding interaction partners.

A TRIM66/DAX1/Dux axis suppresses the totipotent 2-cell-like state in murine embryonic stem cells.

2-cell-like cells (2CLCs)-which comprise only ∼1% of murine embryonic stem cells (mESCs)-resemble blastomeres of 2-cell-stage embryos and are used to investigate zygotic genome activation (ZGA). Here, we discovered that TRIM66 and DAX1 function together as negative regulators of the 2C-like state in mESCs. Chimeric assays confirmed that mESCs lacking TRIM66 or DAX1 function have bidirectional embryonic and extraembryonic differentiation potential.

The CpG Island-Binding Protein SAMD1 Contributes to an Unfavorable Gene Signature in HepG2 Hepatocellular Carcinoma Cells.

The unmethylated CpG island-binding protein SAMD1 is upregulated in many human cancer types, but its cancer-related role has not yet been investigated. Here, we used the hepatocellular carcinoma cell line HepG2 as a cancer model and investigated the cellular and transcriptional roles of SAMD1 using ChIP-Seq and RNA-Seq. SAMD1 targets several thousand gene promoters, where it acts predominantly as a transcriptional repressor.

Evolutionary adaptation of the Polycomb repressive complex 2.

The Polycomb repressive complex 2 (PRC2) is an essential chromatin regulatory complex involved in repressing the transcription of diverse developmental genes. PRC2 consists of a core complex; possessing H3K27 methyltransferase activity and various associated factors that are important to modulate its function. During evolution, the composition of PRC2 and the functionality of PRC2 components have changed considerably.

SUMOylated non-canonical polycomb PRC1.6 complex as a prerequisite for recruitment of transcription factor RBPJ.

Background: Notch signaling controls cell fate decisions in many contexts during development and adult stem cell homeostasis and, when dysregulated, leads to carcinogenesis. The central transcription factor RBPJ assembles the Notch coactivator complex in the presence of Notch signaling, and represses Notch target gene expression in its absence.

Results: We identified L3MBTL2 and additional members of the non-canonical polycomb repressive PRC1.

Making fundamental scientific discoveries by combining information from literature, databases, and computational tools - An example.

In recent years, the amount of available literature, data and computational tools has increased exponentially, providing opportunities and challenges to make use of this vast amount of material. Here, we describe how we utilized publicly available information to identify the previously hardly characterized protein SAMD1 (SAM domain-containing protein 1) as a novel unmethylated CpG island-binding protein. This discovery is an example, how the richness of material and tools on the internet can be used to make scientific breakthroughs, but also the hurdles that may occur.

The SAM domain-containing protein 1 (SAMD1) acts as a repressive chromatin regulator at unmethylated CpG islands.

CpG islands (CGIs) are key regulatory DNA elements at most promoters, but how they influence the chromatin status and transcription remains elusive. Here, we identify and characterize SAMD1 (SAM domain-containing protein 1) as an unmethylated CGI-binding protein. SAMD1 has an atypical winged-helix domain that directly recognizes unmethylated CpG-containing DNA via simultaneous interactions with both the major and the minor groove.

IRF8 Is an AML-Specific Susceptibility Factor That Regulates Signaling Pathways and Proliferation of AML Cells.

Personalized treatment of acute myeloid leukemia (AML) that target individual aberrations strongly improved the survival of AML patients. However, AML is still one of the most lethal cancer diseases of the 21st century, demonstrating the need to find novel drug targets and to explore alternative treatment strategies. Upon investigation of public perturbation data, we identified the transcription factor IRF8 as a novel AML-specific susceptibility gene in humans.

Transcriptional analysis identifies potential biomarkers and molecular regulators in acute malaria infection.

Aims: Malaria is a serious health threat in tropical countries. The causative parasite of Malaria tropica, the severe form, is the protozoan Plasmodium falciparum. In humans, it infects red blood cells, compromising blood flow and tissue perfusion.

The Immunomodulatory Signature of Extracellular Vesicles From Cardiosphere-Derived Cells: A Proteomic and miRNA Profiling.

Experimental data demonstrated that the regenerative potential and immunomodulatory capacity of cardiosphere-derived cells (CDCs) is mediated by paracrine mechanisms. In this process, extracellular vesicles derived from CDCs (EV-CDCs) are key mediators of their therapeutic effect. Considering the future applicability of these vesicles in human diseases, an accurate preclinical-to-clinical translation is needed, as well as an exhaustive molecular characterization of animal-derived therapeutic products.

Epithelial-Mesenchymal Transition in Endometriosis-When Does It Happen?

Epithelial-mesenchymal transition (EMT) is an important process of cell remodeling characterized by the gradual loss of the epithelial phenotype and progressive gain of a mesenchymal phenotype. EMT is not an all-or-nothing process, but instead a transition of epithelial to mesenchymal cells with intermediate cell states. Recently, EMT was described in endometriosis, and many EMT-specific pathways like Twist, Snail, Slug, Zinc finger E-box-binding homeobox 1/2 (ZEB1/2), E/N-cadherin, keratins, and claudins are involved.

Tumor-associated macrophages promote ovarian cancer cell migration by secreting transforming growth factor beta induced (TGFBI) and tenascin C.

A central and unique aspect of high-grade serous ovarian carcinoma (HGSC) is the extensive transcoelomic spreading of tumor cell via the peritoneal fluid or malignant ascites. We and others identified tumor-associated macrophages (TAM) in the ascites as promoters of metastasis-associated processes like extracellular matrix (ECM) remodeling, tumor cell migration, adhesion, and invasion. The precise mechanisms and mediators involved in these functions of TAM are, however, largely unknown.

Transcriptional analysis identifies potential biomarkers and molecular regulators in pneumonia and COPD exacerbation.

Lower respiratory infections, such as community-acquired pneumonia (CAP), and chronic obstructive pulmonary disease (COPD) rank among the most frequent causes of death worldwide. Improved diagnostics and profound pathophysiological insights are urgent clinical needs. In our cohort, we analysed transcriptional networks of peripheral blood mononuclear cells (PBMCs) to identify central regulators and potential biomarkers.

Dual-platform affinity proteomics identifies links between the recurrence of ovarian carcinoma and proteins released into the tumor microenvironment.

The peritoneal fluid (ascites), replete with abundant tumor-promoting factors and extracellular vesicles (EVs) reflecting the tumor secretome, plays an essential role in ovarian high-grade serous carcinoma (HGSC) metastasis and immune suppression. A comprehensive picture of mediators impacting HGSC progression is, however, not available. Proteins in ascites from HGSC patients were quantified by the aptamer-based SOMAscan affinity proteomic platform.

Exosome-dependent immune surveillance at the metastatic niche requires BAG6 and CBP/p300-dependent acetylation of p53.

Extracellular vesicles released by tumor cells contribute to the reprogramming of the tumor microenvironment and interfere with hallmarks of cancer including metastasis. Notably, melanoma cell-derived EVs are able to establish a pre-metastatic niche in distant organs, or on the contrary, exert anti-tumor activity. However, molecular insights into how vesicles are selectively packaged with cargo defining their specific functions remain elusive.

The HRP3 PWWP domain recognizes the minor groove of double-stranded DNA and recruits HRP3 to chromatin.

HDGF-related protein 3 (HRP3, also known as HDGFL3) belongs to the family of HDGF-related proteins (HRPs) and plays an essential role in hepatocellular carcinoma pathogenesis. All HRPs have a PWWP domain at the N-terminus that binds both histone and DNA substrates. Despite previous advances in PWWP domains, the molecular basis by which HRP3 interacts with chromatin is unclear.

Signal peptide peptidase activity connects the unfolded protein response to plant defense suppression by Ustilago maydis.

The corn smut fungus Ustilago maydis requires the unfolded protein response (UPR) to maintain homeostasis of the endoplasmic reticulum (ER) during the biotrophic interaction with its host plant Zea mays (maize). Crosstalk between the UPR and pathways controlling pathogenic development is mediated by protein-protein interactions between the UPR regulator Cib1 and the developmental regulator Clp1. Cib1/Clp1 complex formation results in mutual modification of the connected regulatory networks thereby aligning fungal proliferation in planta, efficient effector secretion with increased ER stress tolerance and long-term UPR activation in planta.

Drosophila melanogaster tPlus3a and tPlus3b ensure full male fertility by regulating transcription of Y-chromosomal, seminal fluid, and heat shock genes.

Spermatogenesis in Drosophila melanogaster is characterized by a specific transcriptional program during the spermatocyte stage. Transcription of thousands of genes is regulated by the interaction of several proteins or complexes, including a tTAF-containing TFIID variant, tMAC, Mediator, and chromatin interactors, e.g.

NF-κB p65 dimerization and DNA-binding is important for inflammatory gene expression.

Increasing evidence shows that many transcription factors execute important biologic functions independent from their DNA-binding capacity. The NF-κB p65 (RELA) subunit is a central regulator of innate immunity. Here, we investigated the relative functional contribution of p65 DNA-binding and dimerization in p65-deficient human and murine cells reconstituted with single amino acid mutants preventing either DNA-binding (p65 E/I) or dimerization (p65 FL/DD).