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Author(s): Amritha Nair [1, 2]; Hsiang-Ching Chung [1, 2, 3]; Tingting Sun [1, 2]; Siddhartha Tyagi [1, 2]; Lacey E Dobrolecki [4]; Rocio Dominguez-Vidana [1, 2, 3]; Sarah J Kurley [...]

The cardiac endothelium influences ventricular chamber development by coordinating trabeculation and compaction. However, the endothelial‐specific molecular mechanisms mediating this coordination are not fully understood. Here, we identify the Sox7 transcription factor as a critical cue instructing cardiac endothelium identity during ventricular chamber development. Endothelial‐specific loss of Sox7 function in mice results in cardiac ventricular defects similar to non‐compaction cardiomyopathy, with a change in the proportions of trabecular and compact cardiomyocytes in the mutant hearts. This phenotype is paralleled by abnormal coronary artery formation. Loss of Sox7 function disrupts the transcriptional regulation of the Notch pathway and connexins 37 and 40, which govern coronary arterial specification. Upon Sox7 endothelial‐specific deletion, single‐nuclei transcriptomics analysis identifies the depletion of a subset of Sox9/Gpc3‐positive endocardial progenitor cells and an increase in erythro‐myeloid cell lineages. Fate mapping analysis reveals that a subset of Sox7‐null endothelial cells transdifferentiate into hematopoietic but not cardiomyocyte lineages. Our findings determine that Sox7 maintains cardiac endothelial cell identity, which is crucial to the cellular cross‐talk that drives ventricular compaction and coronary artery development. Synopsis: Sox7 is essential for endothelial and endocardial differentiation mostly via the modulation of coronary arteries formation and the instruction of cardiac ventricular compaction. Loss of SOX7 function in the cardiac endothelium causes both a lack of distal coronary arteries and a depletion of endocardial progenitors resulting in a non‐compaction cardiomyopathy phenotype.SOX7 maintains a pool of Gpc3/Sox9 double‐positive endocardial cells critical for physiological ventricular maturation and compaction.SOX7 directly modulates Cx40 enhancer activity and regulates arterial differentiation in developing coronary arteries. [ABSTRACT FROM AUTHOR]

MYC (also known as c-MYC) overexpression or hyperactivation is one of the most common drivers of human cancer. Despite intensive study, the MYC oncogene remains recalcitrant to therapeutic inhibition. MYC is a transcription factor, and many of its protumorigenic functions have been attributed to its ability to regulate gene expression programs (1-3). Notably, oncogenic MYC activation has also been shown to increase total RNA and protein production in many tissue and disease contexts (4-7). While such increases in RNA and protein production may endow cancer cells with pro-tumour hallmarks, this increase in synthesis may also generate new or heightened burden on MYC-driven cancer cells to process these macromolecules properly (8). Here we discover that the spliceosome is a new target of oncogenic stress in MYC-driven cancers. We identify BUD31 as a MYC-synthetic lethal gene in human mammary epithelial cells, and demonstrate that BUD31 is a component of the core spliceosome required for its assembly and catalytic activity. Core spliceosomal factors (such as SF3B1 and U2AF1) associated with BUD31 are also required to tolerate oncogenic MYC. Notably, MYC hyperactivation induces an increase in total precursor messenger RNA synthesis, suggesting an increased burden on the core spliceosome to process pre-mRNA. In contrast to normal cells, partial inhibition of the spliceosome in MYC-hyperactivated cells leads to global intron retention, widespread defects in pre-mRNA maturation, and deregulation of many essential cell processes. Notably, genetic or pharmacological inhibition of the spliceosome in vivo impairs survival, tumorigenicity and metastatic proclivity of MYC-dependent breast cancers. Collectively, these data suggest that oncogenic MYC confers a collateral stress on splicing, and that components of the spliceosome may be therapeutic entry points for aggressive MYC-driven cancers., To discover genes and cellular processes required to tolerate oncogenic MYC expression, we previously performed a genome-wide MYC-synthetic lethal screen in human mammary epithelial cells (HMECs) engineered with an inducible [...]

The article describes the case of a 98-year-old woman who was referred for neck ultrasound after a general practitioner (GP) noticed a lump on her neck and was eventually diagnosed with a rare complication of thyroid carcinoma.

Examines DNA dinucleotide evolution in human. Measurement of the length of distribution of human dinucleotide microsatellite loci; Use of mutation model for the analysis; Comparison of results between theory and simulation.

Purpose: Resistance to anti-HER2 therapies in HER2 + breast cancer can occur through activation of alternative survival pathways or reactivation of the HER signaling network. Here we employed BT474 parental and treatment-resistant cell line models to investigate a mechanism by which HER2 + breast cancer can reactivate the HER network under potent HER2-targeted therapies. Experimental Design: Resistant derivatives to lapatinib (L), trastuzumab (T), or the combination (LR/TR/LTR) were developed independently from two independent estrogen receptor ER + /HER2 + BT474 cell lines (AZ/ATCC). Two derivatives resistant to the lapatinib-containing regimens (BT474/AZ-LR and BT474/ATCC-LTR lines) that showed HER2 reactivation at the time of resistance were subjected to massive parallel sequencing and compared with parental lines. Ectopic expression and mutant-specific siRNA interference were applied to analyze the mutation functionally. In vitro and in vivo experiments were performed to test alternative therapies for mutant HER2 inhibition. Results: Genomic analyses revealed that the HER2 L755S mutation was the only common somatic mutation gained in the BT474/AZ-LR and BT474/ATCC-LTR lines. Ectopic expression of HER2 L755S induced acquired lapatinib resistance in the BT474/AZ, SK-BR-3, and AU565 parental cell lines. HER2 L755S-specific siRNA knockdown reversed the resistance in BT474/AZ-LR and BT474/ATCC-LTR lines. The HER1/2-irreversible inhibitors afatinib and neratinib substantially inhibited both resistant cell growth and the HER2 and downstream AKT/MAPK signaling driven by HER2 L755S in vitro and in vivo Conclusions: HER2 reactivation through acquisition of the HER2 L755S mutation was identified as a mechanism of acquired resistance to lapatinib-containing HER2-targeted therapy in preclinical HER2-amplified breast cancer models, which can be overcome by irreversible HER1/2 inhibitors. Clin Cancer Res; 23(17); 5123-34. ©2017 AACR ., (©2017 American Association for Cancer Research.)

Wilms tumor is the most common childhood renal cancer. To identify mutations that predispose to Wilms tumor, we are conducting exome sequencing studies. Here we describe 11 different inactivating mutations in the REST gene (encoding RE1-silencing transcription factor) in four familial Wilms tumor pedigrees and nine non-familial cases. Notably, no similar mutations were identified in the ICR1000 control series (13/558 versus 0/993; P < 0.0001) or in the ExAC series (13/558 versus 0/61,312; P < 0.0001). We identified a second mutational event in two tumors, suggesting that REST may act as a tumor-suppressor gene in Wilms tumor pathogenesis. REST is a zinc-finger transcription factor that functions in cellular differentiation and embryonic development. Notably, ten of 11 mutations clustered within the portion of REST encoding the DNA-binding domain, and functional analyses showed that these mutations compromise REST transcriptional repression. These data establish REST as a Wilms tumor predisposition gene accounting for ∼2% of Wilms tumor.

Identification of the host genetic factors that contribute to variation in vaccine responsiveness may uncover important mechanisms affecting vaccine efficacy. We carried out an integrative, longitudinal study combining genetic, transcriptional, and immunologic data in humans given seasonal influenza vaccine. We identified 20 genes exhibiting a transcriptional response to vaccination, significant genotype effects on gene expression, and correlation between the transcriptional and antibody responses. The results show that variation at the level of genes involved in membrane trafficking and antigen processing significantly influences the human response to influenza vaccination. More broadly, we demonstrate that an integrative study design is an efficient alternative to existing methods for the identification of genes involved in complex traits. DOI:http://dx.doi.org/10.7554/eLife.00299.001., Competing Interests: The authors declare that no competing interests exist.