Fatty acid (FA) uptake and altered metabolism constitute hallmarks of metastasis 1-2 yet it is unclear the biology behind it, or whether all dietary FAs are prometastatic. Here we show that dietary palmitic acid (PA), but not oleic acid or linoleic acid, promotes metastasis in oral carcinomas and melanoma. Unexpectedly, tumours from mice fed a short-term palm oil (PA)-rich diet, or tumour cells briefly exposed to PA in vitro, remain highly metastatic even when serially transplanted (without further exposure to high levels of PA). This PAinduced prometastatic memory requires the fatty acid transporter CD36 and is associated with the stable deposition of histone H3 lysine 4 trimethylation by the methyltransferase Set1A/COMPASS. Bulk, single-cell and positional RNA sequencing indicate that genes with this prometastatic memory predominantly relate to a neural signature that stimulates intratumour Schwann cells and innervation, two parameters strongly correlated with metastasis but etiologically poorly understood 3-4 . Mechanistically, tumour-associated Schwann cells secrete a specialized pro-regenerative extracellular matrix, whose ablation inhibits metastasis initiation. Both the PA-induced memory of this proneural signature and its long-term boost in metastasis require the transcription factor EGR2 and the glial cellstimulating peptide galanin. In sum, we provide evidence that a dietary metabolite provokes stable transcriptional and chromatin changes that lead to a long-term stimulation of metastasis, and that this is related to a pro-regenerative state of tumour-activated Schwann cells.
The coordinated tissue-specific regulation of gene expression is essential for the proper development of all organisms. Mutations in multiple transcriptional regulators cause a group of neurodevelopmental disorders termed "transcriptomopathies" that share core phenotypical features including growth retardation, developmental delay, intellectual disability and facial dysmorphism. Cornelia de Lange syndrome (CdLS) belongs to this class of disorders and is caused by mutations in different subunits or regulators of the cohesin complex. Herein, we report on the clinical and molecular characterization of seven patients with features overlapping with CdLS who were found to carry mutations in chromatin regulators previously associated to other neurodevelopmental disorders that are frequently considered in the differential diagnosis of CdLS. The identified mutations affect the methyltransferase-encoding genes KMT2A and SETD5 and different subunits of the SWI/SNF chromatin-remodeling complex. Complementary to this, a patient with Coffin-Siris syndrome was found to carry a missense substitution in NIPBL. Our findings indicate that mutations in a variety of chromatin-associated factors result in overlapping clinical phenotypes, underscoring the genetic heterogeneity that should be considered when assessing the clinical and molecular diagnosis of neurodevelopmental syndromes. It is clear that emerging molecular mechanisms of chromatin dysregulation are central to understanding the pathogenesis of these clinically overlapping genetic disorders.
Highlights d The NIPBL-MAU2 interaction is required for the stability of both proteins d A pathogenic MAU2 deletion impairs dimerization and causes NIPBL haploinsufficiency d Early frameshift mutations in NIPBL induce alternative translation initiation d Translation re-initiation rescues NIPBL expression and renders MAU2 dispensable
CD4 and CD8 mark helper and cytotoxic T cell lineages, respectively, and serve as coreceptors for MHC-restricted TCR recognition. How coreceptor expression is matched with TCR specificity is central to understanding CD4/CD8 lineage choice, but visualising coreceptor gene activity in individual selection intermediates has been technically challenging. It therefore remains unclear whether the sequence of coreceptor gene expression in selection intermediates follows a stereotypic pattern, or is responsive to signaling. Here we use single cell RNA sequencing (scRNA-seq) to classify mouse thymocyte selection intermediates by coreceptor gene expression. In the unperturbed thymus, Cd4+Cd8a- selection intermediates appear before Cd4-Cd8a+ selection intermediates, but the timing of these subsets is flexible according to the strength of TCR signals. Our data show that selection intermediates discriminate MHC class prior to the loss of coreceptor expression and suggest a model where signal strength informs the timing of coreceptor gene activity and ultimately CD4/CD8 lineage choice.
Cornelia de Lange syndrome (CdLS) is a dominantly inherited developmental disorder caused by mutations in genes that encode for either structural (SMC1A, SMC3, RAD21) or regulatory (NIPBL, HDAC8) subunits of the cohesin complex. NIPBL represents the major gene of the syndrome and heterozygous mutations can be identified in more than 65% of patients. Interestingly, large portions of these variants were described as somatic mosaicism and often escape standard molecular diagnostics using lymphocyte DNA. Here we discuss the role of somatic mosaicism in CdLS and describe two additional patients with NIPBL mosaicism detected by targeted gene panel or exome sequencing. In order to verify the next generation sequencing data, Sanger sequencing or pyrosequencing on DNA extracted from different tissues were applied. None of the pathogenic variants was originally detected by Sanger sequencing on blood DNA. Patient 1 displays an unusual combination of clinical features: he is cognitively only mildly affected, but shows severe limb reduction defects. Patient 2 presents with a moderate phenotype. Interestingly, Sanger sequencing analysis on fibroblast DNA of this patient did not detect the disease-causing variant previously observed on the same DNA sample by exome sequencing. Subsequent analyses could confirm the variants by Sanger sequencing on buccal mucosa DNA. Notably, this is the first report of a higher mutational load in buccal mucosa than in fibroblast cells of a CdLS patient. Detection of low-level mosaicism is of utmost importance for an accurate molecular diagnosis and a proper genetic counseling of patients with a clinical diagnosis of CdLS. Next-generation sequencing technologies greatly facilitate the detection of low-level mosaicism, which might otherwise remain undetected by conventional sequencing approaches.
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