34 research outputs found
Mammary molecular portraits reveal lineage-specific features and progenitor cell vulnerabilities.
The mammary epithelium depends on specific lineages and their stem and progenitor function to accommodate hormone-triggered physiological demands in the adult female. Perturbations of these lineages underpin breast cancer risk, yet our understanding of normal mammary cell composition is incomplete. Here, we build a multimodal resource for the adult gland through comprehensive profiling of primary cell epigenomes, transcriptomes, and proteomes. We define systems-level relationships between chromatin-DNA-RNA-protein states, identify lineage-specific DNA methylation of transcription factor binding sites, and pinpoint proteins underlying progesterone responsiveness. Comparative proteomics of estrogen and progesterone receptor-positive and -negative cell populations, extensive target validation, and drug testing lead to discovery of stem and progenitor cell vulnerabilities. Top epigenetic drugs exert cytostatic effects; prevent adult mammary cell expansion, clonogenicity, and mammopoiesis; and deplete stem cell frequency. Select drugs also abrogate human breast progenitor cell activity in normal and high-risk patient samples. This integrative computational and functional study provides fundamental insight into mammary lineage and stem cell biology
The Effect of Chromosome 9p21 Variants on Cardiovascular Disease May Be Modified by Dietary Intake: Evidence from a Case/Control and a Prospective Study
Peer reviewe
Meta-analysis of Dense Genecentric Association Studies Reveals Common and Uncommon Variants Associated with Height (vol 88, pg 6, 2010)
Concept, Design and Implementation of a Cardiovascular Gene-Centric 50 K SNP Array for Large-Scale Genomic Association Studies
A wealth of genetic associations for cardiovascular and metabolic phenotypes in humans has been accumulating over the last decade, in particular a large number of loci derived from recent genome wide association studies (GWAS). True complex disease-associated loci often exert modest effects, so their delineation currently requires integration of diverse phenotypic data from large studies to ensure robust meta-analyses. We have designed a gene-centric 50 K single nucleotide polymorphism (SNP) array to assess potentially relevant loci across a range of cardiovascular, metabolic and inflammatory syndromes. The array utilizes a âcosmopolitanâ tagging approach to capture the genetic diversity across âŒ2,000 loci in populations represented in the HapMap and SeattleSNPs projects. The array content is informed by GWAS of vascular and inflammatory disease, expression quantitative trait loci implicated in atherosclerosis, pathway based approaches and comprehensive literature searching. The custom flexibility of the array platform facilitated interrogation of loci at differing stringencies, according to a gene prioritization strategy that allows saturation of high priority loci with a greater density of markers than the existing GWAS tools, particularly in African HapMap samples. We also demonstrate that the IBC array can be used to complement GWAS, increasing coverage in high priority CVD-related loci across all major HapMap populations. DNA from over 200,000 extensively phenotyped individuals will be genotyped with this array with a significant portion of the generated data being released into the academic domain facilitating in silico replication attempts, analyses of rare variants and cross-cohort meta-analyses in diverse populations. These datasets will also facilitate more robust secondary analyses, such as explorations with alternative genetic models, epistasis and gene-environment interactions
Meta-analysis of Dense Genecentric Association Studies Reveals Common and Uncommon Variants Associated with Height
Height is a classic complex trait with common variants in a growing list of genes known to contribute to the phenotype. Using a genecentric genotyping array targeted toward cardiovascular-related loci, comprising 49,320 SNPs across approximately 2000 loci, we evaluated the association of common and uncommon SNPs with adult height in 114,223 individuals from 47 studies and six ethnicities. A total of 64 loci contained a SNP associated with height at array-wide significance (p < 2.4 Ă 10â6), with 42 loci surpassing the conventional genome-wide significance threshold (p < 5 Ă 10â8). Common variants with minor allele frequencies greater than 5% were observed to be associated with height in 37 previously reported loci. In individuals of European ancestry, uncommon SNPs in IL11 and SMAD3, which would not be genotyped with the use of standard genome-wide genotyping arrays, were strongly associated with height (p < 3 Ă 10â11). Conditional analysis within associated regions revealed five additional variants associated with height independent of lead SNPs within the locus, suggesting allelic heterogeneity. Although underpowered to replicate findings from individuals of European ancestry, the direction of effect of associated variants was largely consistent in African American, South Asian, and Hispanic populations. Overall, we show that dense coverage of genes for uncommon SNPs, coupled with large-scale meta-analysis, can successfully identify additional variants associated with a common complex trait
The transcriptional landscape of Shh medulloblastoma
© The Author(s) 2021. Open Access. This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the articleâs Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the articleâs Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.Sonic hedgehog medulloblastoma encompasses a clinically and molecularly diverse group of cancers of the developing central nervous system. Here, we use unbiased sequencing of the transcriptome across a large cohort of 250 tumors to reveal differences among molecular subtypes of the disease, and demonstrate the previously unappreciated importance of non-coding RNA transcripts. We identify alterations within the cAMP dependent pathway (GNAS, PRKAR1A) which converge on GLI2 activity and show that 18% of tumors have a genetic event that directly targets the abundance and/or stability of MYCN. Furthermore, we discover an extensive network of fusions in focally amplified regions encompassing GLI2, and several loss-of-function fusions in tumor suppressor genes PTCH1, SUFU and NCOR1. Molecular convergence on a subset of genes by nucleotide variants, copy number aberrations, and gene fusions highlight the key roles of specific pathways in the pathogenesis of Sonic hedgehog medulloblastoma and open up opportunities for therapeutic intervention.info:eu-repo/semantics/publishedVersio
Failure of human rhombic lip differentiation underlies medulloblastoma formation
Medulloblastoma (MB) comprises a group of heterogeneous paediatric embryonal neoplasms of the hindbrain with strong links to early development of the hindbrain 1â4. Mutations that activate Sonic hedgehog signalling lead to Sonic hedgehog MB in the upper rhombic lip (RL) granule cell lineage 5â8. By contrast, mutations that activate WNT signalling lead to WNT MB in the lower RL 9,10. However, little is known about the more commonly occurring group 4 (G4) MB, which is thought to arise in the unipolar brush cell lineage 3,4. Here we demonstrate that somatic mutations that cause G4 MB converge on the core binding factor alpha (CBFA) complex and mutually exclusive alterations that affect CBFA2T2, CBFA2T3, PRDM6, UTX and OTX2. CBFA2T2 is expressed early in the progenitor cells of the cerebellar RL subventricular zone in Homo sapiens, and G4 MB transcriptionally resembles these progenitors but are stalled in developmental time. Knockdown of OTX2 in model systems relieves this differentiation blockade, which allows MB cells to spontaneously proceed along normal developmental differentiation trajectories. The specific nature of the split human RL, which is destined to generate most of the neurons in the human brain, and its high level of susceptible EOMES +KI67 + unipolar brush cell progenitor cells probably predisposes our species to the development of G4 MB
Genetic insights into obesity and its associated metabolic complications: a multiethnic perspective
Obesity has become one of the biggest threats to global health, as it frequently co-occurs with a constellation of type 2 diabetes (T2D) and cardiovascular disease (CVD) risk factors and is associated with increased mortality. Genetic factors account for a substantial portion of the phenotypic variance in obesity and each of the correlated vascular disease risk factors. In this thesis, I describe the identification of several common genetic variants that predispose carriers to the complications associated with obesity. First, I report the identification of common variation within the gene of a protein secreted by visceral adipose tissue, visfatin, and demonstrate the influence of these variants on the inter-individual variation in fasting insulin levels. Second, I describe the identification of an interaction between the use of thiazolidinediones (TZDs), a class of anti-hyperglycemic medication, and variation in the nuclear factor of activated T-cells cytoplasmic component 2 (NFATC2) gene that results in edema and potentially congestive heart failure (CHF). Next, using a South Asian population sample for gene discovery, I identify a novel association between variation in the dipeptidyl peptidase 4 (DPP4) gene, a target of incretin-based anti-hyperglycemic medication, and apolipoprotein B (apoB) levels, a CVD risk factor and marker of the dyslipidemia associated with obesity. In addition, using observed differences between the Europeans and South Asians I was able to identify heterogeneity in the association between DPP4 and apoB caused by adiposity. Finally, I report an association between variation in the sterol regulatory element binding protein 1 (SREBF1) gene and body mass index (BMI) and demonstrate its potential contribution to observed differences in BMI among different ethnicities around the world. I also present data that strongly suggest that these differences may have been due to recent positive selection at this locus in human populations. The findings in this thesis illustrate the importance of common genetic variants in the pathogenesis of obesity, as well as its associated complications and highlight the regulation of glucose by adipose tissue as an important underlying feature.L'obĂ©sitĂ© est devenue une des plus grandes menaces dans la santĂ© publique, Ă©tant donnĂ© qu'elle est frĂ©quemment co-reliĂ©e avec des facteurs de risque du diabĂšte de type 2 (T2D) et de la maladie cardiovasculaire (CVD), et est donc associĂ©e Ă une mortalitĂ© accrue. Les facteurs gĂ©nĂ©tiques reprĂ©sentent une partie substantielle de la variation phĂ©notypique de l'obĂ©sitĂ©, ainsi que des facteurs de risque des maladies vasculaires qui y sont associĂ©s. Dans cette thĂšse, je dĂ©cris l'identification de plusieurs variants gĂ©nĂ©tiques communs qui prĂ©disposent les porteurs aux complications associĂ©es Ă l'obĂ©sitĂ©. D'abord, je dĂ©cris l'identification d'une variation commune dans le gĂšne d'une protĂ©ine sĂ©crĂ©tĂ©e par le tissu adipeux viscĂ©ral, visfatin, et dĂ©montre l'influence de ces variants sur la variation interindividuelle d'une insulinĂ©mie Ă jeun. DeuxiĂšmement, je dĂ©cris l'identification d'une interaction entre l'utilisation des thiazolidinediones une classe de mĂ©dicaments anti-hyperglycĂ©miques, et une variation gĂ©nĂ©tique dans le gĂšne nuclear factor of activated T-cells cytoplasmic component 2 (NFATC2) qui aboutit Ă l'ĆdĂšme et potentiellement Ă l'insuffisance cardiaque congestive. Ensuite, en utilisant un Ă©chantillon de la population asiatique du Sud dans la dĂ©couverte de gĂšnes, j'identifie une nouvelle association entre la variation du gĂšne dipeptidyl peptidase 4 (DPP4), une cible de la mĂ©dication anti-hyperglycĂ©mique basĂ©e sur l'incretin, et les niveaux de l'apolipoprotĂ©ine B (apoB), un facteur de risque du CVD et un marqueur de la dyslipidĂ©mie associĂ©e Ă l'obĂ©sitĂ©. De plus, en utilisant des diffĂ©rences observĂ©es entre les EuropĂ©ens et les Asiatiques du Sud, j'ai pu identifier l'hĂ©tĂ©rogĂ©nĂ©itĂ© dans l'association entre DPP4 et apoB causĂ© par l'adipositĂ©. Finalement, je dĂ©cris une association entre la variation du gĂšne sterol regulatory element binding protein 1 (SREBF1) et l'indice de masse corporelle (BMI) et dĂ©montre sa contribution potentielle aux diffĂ©rences de BMI observĂ©es parmi diffĂ©rentes ethnicitĂ©s dans le monde entier. Je prĂ©sente aussi des donnĂ©es qui suggĂšrent fortement que ces diffĂ©rences peuvent ĂȘtre dues Ă une rĂ©cente sĂ©lection positive Ă ce locus dans des populations humaines. Les dĂ©couvertes de cette thĂšse illustrent l'importance des variants gĂ©nĂ©tiques communs dans la pathogenĂšse de l'obĂ©sitĂ©, ainsi que les complications qui s'y rattachent et mettent en Ă©vidence la rĂ©gulation de glucose par le tissu adipeux comme Ă©tant une caractĂ©ristique sous-jacente importante
Enhancer alterations in cancer: a source for a cell identity crisis
Abstract
Enhancers are selectively utilized to orchestrate gene expression programs that first govern pluripotency and then proceed to highly specialized programs required for the process of cellular differentiation. Whereas gene-proximal promoters are typically active across numerous cell types, distal enhancer activation is cell-type-specific and central to cell fate determination, thereby accounting for cell identity. Recent studies have highlighted the diversity of enhancer usage, cataloguing millions of such elements in the human genome. The disruption of enhancer activity, through genetic or epigenetic alterations, can impact cell-type-specific functions, resulting in a wide range of pathologies. In cancer, these alterations can promote a `cell identity crisis, in which enhancers associated with oncogenes and multipotentiality are activated, while those promoting cell fate commitment are inactivated. Overall, these alterations favor an undifferentiated cellular phenotype. Here, we review the current knowledge regarding the role of enhancers in normal cell function, and discuss how genetic and epigenetic changes in enhancer elements potentiate oncogenesis. In addition, we discuss how understanding the mechanisms regulating enhancer activity can inform therapeutic opportunities in cancer cells and highlight key challenges that remain in understanding enhancer biology as it relates to oncology