We conducted the largest investigation of predisposition variants in cancer to date, discovering 853 pathogenic or likely pathogenic variants in 8% of 10,389 cases from 33 cancer types. Twenty-one genes showed single or cross-cancer associations, including novel associations of SDHA in melanoma and PALB2 in stomach adenocarcinoma. The 659 predisposition variants and 18 additional large deletions in tumor suppressors, including ATM, BRCA1, and NF1, showed low gene expression and frequent (43%) loss of heterozygosity or biallelic two-hit events. We also discovered 33 such variants in oncogenes, including missenses in MET, RET, and PTPN11 associated with high gene expression. We nominated 47 additional predisposition variants from prioritized VUSs supported by multiple evidences involving case-control frequency, loss of heterozygosity, expression effect, and co-localization with mutations and modified residues. Our integrative approach links rare predisposition variants to functional consequences, informing future guidelines of variant classification and germline genetic testing in cancer.
We report that MOP3 is a general dimerization partner for a subset of the basic-helix-loop-helix (bHLH) The PAS domain is found in a variety of proteins that play roles in development and adaptation to the environment (1-6). The PAS domain is also commonly found in proteins that harbor basic-helix-loop-helix (bHLH) domains, and that act in pairs as heterodimeric transcription factors (6-8). For example, the aryl hydrocarbon receptor nuclear translocator (ARNT) protein has been shown to act as a general partner for a number structurally related proteins that appear to act as sensors for environmental stimuli. ARNT dimerizes with the aryl hydrocarbon receptor (AHR) and mediates metabolic responses to 2,3,7,8-tetrachlorodibenzo-p-dioxin and related environmental contaminants. ARNT also dimerizes with hypoxiainducible factor 1␣ (HIF1␣) and mediates cellular responses to low oxygen and glucose (2, 6).-Recently, a number of ''orphan'' bHLH-PAS proteins have emerged from searches of expressed sequence tag databases and low stringency hybridization screens (9-14). For newly discovered bHLH-PAS proteins that have close homologs (e.g., HIF1␣ and HIF2␣ § or ARNT and ARNT2), partnering and DNA binding specificity can often be predicted from amino acid sequence similarities in their bHLH-PAS domains (9,12,14). For divergent orphans like MOP3, MOP4, and MOP5, amino acid sequence does not provide the information necessary for similar predictions. In an attempt to characterize this class of orphans, we have employed a series of assays that allow us to: (i) identify heterodimeric partnerships, (ii) determine the DNA response element bound by these heterodimers, (iii) verify that these complexes drive transcription in mammalian cells, and (iv) identify those tissues where these partnerships may occur. This report describes application of this approach to two bHLH-PAS orphans, MOP3 and MOP4.
Normal spermatogenesis is essential for reproduction and depends on proper spermatogonial stem cell (SSC) function. Genes and signaling pathways that regulate SSC function have not been well defined. We report that glial cell-line-derived neurotrophic factor (GDNF) signaling through the RET tyrosine kinase/GFRA1 receptor complex is required for spermatogonial self-renewal in mice. GFRA1 and RET expression was identified in a subset of gonocytes at birth, was restricted to SSCs during normal spermatogenesis, and RET expressing cells were abundant in a cryptorchid model of SSC self-renewal. We used the whole-testis transplantation technique to overcome the limitation of neonatal lethality of Gdnf-, Gfra1-, and Ret-deficient mice and found that each of these genes is required for postnatal spermatogenesis and not for embryological testes development. Each mutant testis shows severe SSC depletion by Postnatal Day 7 during the first wave of spermatogenesis. These defects were due to lack of SSC proliferation and an inability of SSCs to maintain an undifferentiated state. Our results demonstrate that GDNF-mediated RET signaling is critical for the fate of undifferentiated spermatogonia and that abnormalities in this pathway may contribute to male infertility and testicular germ cell tumors.
Defining cellular and molecular identities within the kidney is necessary to understand its organization and function in health and disease. Here we demonstrate a reproducible method with minimal artifacts for single-nucleus Droplet-based RNA sequencing (snDrop-Seq) that we use to resolve thirty distinct cell populations in human adult kidney. We define molecular transition states along more than ten nephron segments spanning two major kidney regions. We further delineate cell type-specific expression of genes associated with chronic kidney disease, diabetes and hypertension, providing insight into possible targeted therapies. This includes expression of a hypertension-associated mechano-sensory ion channel in mesangial cells, and identification of proximal tubule cell populations defined by pathogenic expression signatures. Our fully optimized, quality-controlled transcriptomic profiling pipeline constitutes a tool for the generation of healthy and diseased molecular atlases applicable to clinical samples.
Mesenchymal stem cell-like (MSC-like) cells reside in the vascular wall but their role in vascular regeneration and disease is poorly understood. Here, we show that Gli1+ cells located in the arterial adventitia are progenitors of vascular smooth muscle cells, and contribute to neointima formation and repair after acute injury to the femoral artery. Genetic fate tracing indicates that adventitial Gli1+ MSC-like cells migrate into the media and neointima during athero- and arteriosclerosis in ApoE−/− mice with chronic kidney disease. Our data indicate that Gli1+ cells are a major source of osteoblast-like cells during calcification in the media and intima. Genetic ablation of Gli1+ cells before induction of kidney injury dramatically reduced the severity of vascular calcification. These findings implicate Gli1+ cells as critical adventitial progenitors in vascular remodeling after acute and during chronic injury and suggest that they may be relevant therapeutic targets for mitigation of vascular calcification.
In an attempt to identify cofactors that could possibly influence the transcriptional activity of peroxisome proliferator-activated receptors (PPARs), we used a yeast two-hybrid system with Gal4-PPAR␥ as bait to screen a mouse liver cDNA library and have identified steroid receptor coactivator-1 (SRC-1) as a PPAR transcriptional coactivator. We now report the isolation of a cDNA encoding a 165-kDa PPAR␥-binding protein, designated PBP which also serves as a coactivator. PBP also binds to PPAR␣, RAR␣, RXR, and TR1, and this binding is increased in the presence of specific ligands. Deletion of the last 12 amino acids from the carboxyl terminus of PPAR␥ results in the abolition of interaction between PBP and PPAR␥. PBP modestly increased the transcriptional activity of PPAR␥, and a truncated form of PBP (amino acids 487-735) acted as a dominantnegative repressor, suggesting that PBP is a genuine coactivator for PPAR. In addition, PBP contains two LXXLL signature motifs considered necessary and sufficient for the binding of several coactivators to nuclear receptors. In situ hybridization and Northern analysis showed that PBP is expressed in many tissues of adult mice, including the germinal epithelium of testis, where it appeared most abundant, and during ontogeny, suggesting a possible role for this cofactor in cellular proliferation and differentiation.The peroxisome proliferator-activated receptors (PPARs) 1 are a group of transcription factors that regulate the expression of target genes, in particular those associated with lipid metabolism (1, 2). PPARs, which derive the designation by virtue of their ability to mediate predictable pleiotropic effects in response to peroxisome proliferators (1,3,4), are members of the nuclear receptor superfamily (5, 6). Three isotypes of PPARs, namely PPAR␣, PPAR␦ (also called  or NUC-1), and PPAR␥ have been identified as products of separate genes from Xenopus, rodents, and humans (1, 7-12). These PPAR isotypes appear to exhibit distinct patterns of tissue distribution and differ considerably in their ligand binding domains, suggesting that they possibly perform different functions in different cell types (7,13,14). Indeed, of the three isotypes, PPAR␣ expression is relatively high in hepatocytes, enterocytes, and the proximal tubular epithelium of kidney when compared with other cell types (13,14), and evidence derived from mice with PPAR␣ gene disruption indicates that this receptor is essential for the pleiotropic responses induced by peroxisome proliferators (15). Several structurally diverse peroxisome proliferators, specific fatty acids, and eicosanoids act as ligands for PPAR␣ (4, 16 -19). Although PPAR␦ isotype is ubiquitously expressed and binds the same ligands as PPAR␣ (18,19), its functional significance remains largely elusive. PPAR␥ exists as two isoforms, PPAR␥1 and PPAR␥2, as a consequence of alternate promoter usage in the gene encoding this receptor (8,20,21). While PPAR␥1 isoform expression is restricted to liver and few other organs (8, 14), the PPAR␥2 i...
GDNF signaling through the Ret receptor tyrosine kinase is critical for ureteric bud branching morphogenesis during kidney development, yet few of the downstream genes are currently known. We find that the ETS transcription factors Etv4 and Etv5 are positively regulated by Ret signaling in the ureteric bud tips. Etv4−/−, Etv5+/− mice display either renal agenesis or severe hypodysplasia, while kidney development fails completely in double homozygotes. We identify several genes whose expression in the ureteric bud depends on Etv4 and Etv5, including Cxcr4, Myb, Met, Mmp14. Thus, Etv4 and Etv5 are key components of a gene network downstream of Ret that promotes and controls renal branching morphogenesis.
The basic helix-loop-helix-PAS (bHLH-PAS) protein ARNT is a dimeric partner of the Ah receptor (AHR) and hypoxia inducible factor 1 alpha(HIF1 alpha). These dimers mediate biological responses to xenobiotic exposure and low oxygen tension. The recent cloning of ARNT and HIF1(homologues (ARNT2 and HIF2 alpha) indicates that at least six distinct bHLH-PAS heterodimeric combinations can occur in response to a number of environmental stimuli. In an effort to understand the biological relevance of this combinatorial complexity, we characterized their relative expression at a number of developmental time points by parallel in situ hybridization of adjacent tissue sections. Our results reveal that in general there is limited redundancy in the expression of these six transcription factors and that each of these bHLH-PAS members displays a unique pattern of developmental expression emerging as early as embryonic day 9.5.
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