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Dive into the research topics where Marcelo A. Nobrega is active.

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Featured researches published by Marcelo A. Nobrega.


Nature | 2006

In vivo enhancer analysis of human conserved non-coding sequences.

Len A. Pennacchio; Nadav Ahituv; Alan M. Moses; Shyam Prabhakar; Marcelo A. Nobrega; Malak Shoukry; Simon Minovitsky; Inna Dubchak; Amy Holt; Keith D. Lewis; Ingrid Plajzer-Frick; Jennifer A. Akiyama; Sarah De Val; Veena Afzal; Brian L. Black; Olivier Couronne; Michael B. Eisen; Axel Visel; Edward M. Rubin

Identifying the sequences that direct the spatial and temporal expression of genes and defining their function in vivo remains a significant challenge in the annotation of vertebrate genomes. One major obstacle is the lack of experimentally validated training sets. In this study, we made use of extreme evolutionary sequence conservation as a filter to identify putative gene regulatory elements, and characterized the in vivo enhancer activity of a large group of non-coding elements in the human genome that are conserved in human–pufferfish, Takifugu (Fugu) rubripes, or ultraconserved in human–mouse–rat. We tested 167 of these extremely conserved sequences in a transgenic mouse enhancer assay. Here we report that 45% of these sequences functioned reproducibly as tissue-specific enhancers of gene expression at embryonic day 11.5. While directing expression in a broad range of anatomical structures in the embryo, the majority of the 75 enhancers directed expression to various regions of the developing nervous system. We identified sequence signatures enriched in a subset of these elements that targeted forebrain expression, and used these features to rank all ∼3,100 non-coding elements in the human genome that are conserved between human and Fugu. The testing of the top predictions in transgenic mice resulted in a threefold enrichment for sequences with forebrain enhancer activity. These data dramatically expand the catalogue of human gene enhancers that have been characterized in vivo, and illustrate the utility of such training sets for a variety of biological applications, including decoding the regulatory vocabulary of the human genome.


Nature | 2014

Obesity-associated variants within FTO form long-range functional connections with IRX3

Scott Smemo; Juan J. Tena; Kyoung-Han Kim; Eric R. Gamazon; Noboru Jo Sakabe; Carlos Gómez-Marín; Ivy Aneas; Flavia L. Credidio; Débora Rodrigues Sobreira; Nora F. Wasserman; Ju Hee Lee; Vijitha Puviindran; Davis Tam; Michael Shen; Joe Eun Son; Niki Alizadeh Vakili; Hoon-Ki Sung; Silvia Naranjo; Rafael D. Acemel; Miguel Manzanares; Andras Nagy; Nancy J. Cox; Chi-chung Hui; José Luis Gómez-Skarmeta; Marcelo A. Nobrega

Genome-wide association studies (GWAS) have reproducibly associated variants within introns of FTO with increased risk for obesity and type 2 diabetes (T2D). Although the molecular mechanisms linking these noncoding variants with obesity are not immediately obvious, subsequent studies in mice demonstrated that FTO expression levels influence body mass and composition phenotypes. However, no direct connection between the obesity-associated variants and FTO expression or function has been made. Here we show that the obesity-associated noncoding sequences within FTO are functionally connected, at megabase distances, with the homeobox gene IRX3. The obesity-associated FTO region directly interacts with the promoters of IRX3 as well as FTO in the human, mouse and zebrafish genomes. Furthermore, long-range enhancers within this region recapitulate aspects of IRX3 expression, suggesting that the obesity-associated interval belongs to the regulatory landscape of IRX3. Consistent with this, obesity-associated single nucleotide polymorphisms are associated with expression of IRX3, but not FTO, in human brains. A direct link between IRX3 expression and regulation of body mass and composition is demonstrated by a reduction in body weight of 25 to 30% in Irx3-deficient mice, primarily through the loss of fat mass and increase in basal metabolic rate with browning of white adipose tissue. Finally, hypothalamic expression of a dominant-negative form of Irx3 reproduces the metabolic phenotypes of Irx3-deficient mice. Our data suggest that IRX3 is a functional long-range target of obesity-associated variants within FTO and represents a novel determinant of body mass and composition.


Journal of Biological Chemistry | 2002

Gene Expression Profiling Leads to Identification of GLI1-binding Elements in Target Genes and a Role for Multiple Downstream Pathways in GLI1-induced Cell Transformation

Joon Won Yoon; Yasuhiro Kita; Daniel J. Frank; Rebecca R. Majewski; Beth A. Konicek; Marcelo A. Nobrega; Howard J. Jacob; David Walterhouse; Philip M. Iannaccone

The zinc finger transcription factor GLI1, which mediates Sonic hedgehog signaling during development, is expressed in several human cancers, including basal cell carcinoma, medulloblastoma, and sarcomas. We identified 147 genes whose levels of expression were significantly altered in RNA obtained from cells demonstrating a transformed phenotype with stable GLI1 expression or stableHa-ras expression. Comparison of expression profiles fromGLI1- and Ha-ras-expressing cells established a set of genes unique to GLI1-induced cell transformation. Thirty genes were altered by stable GLI1 expression, and 124 genes were changed by stable Ha-ras expression. Seven genes had altered expression levels in both GLI1- andHa-ras-expressing cells. Genes whose expression was altered by GLI1 included cell cycle genes, cell adhesion genes, signal transduction genes, and genes regulating apoptosis. GLI1 consensus DNA-binding sequences were identified in the 5′ regions of cyclin D2, IGFBP-6, osteopontin, and plakoglobin, suggesting that these genes represent immediate downstream targets. Gel shift analysis confirmed the ability of the GLI1 protein to bind these sequences. Up-regulation of cyclin D2 and down-regulation of plakoglobin were demonstrated in GLI1-amplified compared with non-amplified human rhabdomyosarcoma cells. Many of theGLI1 targets with known function identified in this study increase cell proliferation, indicating that GLI1-induced cell transformation occurs through multiple downstream pathways.


Nature Reviews Genetics | 2004

Comparative genomics at the vertebrate extremes

Dario Boffelli; Marcelo A. Nobrega; Edward M. Rubin

Annotators of the human genome are increasingly exploiting comparisons with genomes at both the distal and proximal evolutionary edges of the vertebrate tree. Despite the sequence similarity between primates, comparisons among members of this clade are beginning to identify primate- as well as human-specific functional elements. At the distal evolutionary extreme, comparing the human genome to that of non-mammal vertebrates such as fish has proved to be a powerful filter to prioritize sequences that most probably have significant functional activity in all vertebrates.


Journal of Medical Genetics | 2009

Further delineation of the 15q13 microdeletion and duplication syndromes: a clinical spectrum varying from non-pathogenic to a severe outcome

B.W.M. van Bon; Mefford Hc; Björn Menten; David A. Koolen; Andrew J. Sharp; Willy M. Nillesen; Jeffrey W. Innis; T. de Ravel; Catherine Mercer; Marco Fichera; Helen Stewart; L E Connell; Katrin Õunap; Katherine Lachlan; B Castle; N. Van der Aa; C.M.A. van Ravenswaaij; Marcelo A. Nobrega; C Serra-Juhé; Ingrid Simonic; N. de Leeuw; Rolph Pfundt; Ernie M.H.F. Bongers; Carl Baker; P Finnemore; S Huang; Viv Maloney; John A. Crolla; M van Kalmthout; Maurizio Elia

Background: Recurrent 15q13.3 microdeletions were recently identified with identical proximal (BP4) and distal (BP5) breakpoints and associated with mild to moderate mental retardation and epilepsy. Methods: To assess further the clinical implications of this novel 15q13.3 microdeletion syndrome, 18 new probands with a deletion were molecularly and clinically characterised. In addition, we evaluated the characteristics of a family with a more proximal deletion between BP3 and BP4. Finally, four patients with a duplication in the BP3–BP4–BP5 region were included in this study to ascertain the clinical significance of duplications in this region. Results: The 15q13.3 microdeletion in our series was associated with a highly variable intra- and inter-familial phenotype. At least 11 of the 18 deletions identified were inherited. Moreover, 7 of 10 siblings from four different families also had this deletion: one had a mild developmental delay, four had only learning problems during childhood, but functioned well in daily life as adults, whereas the other two had no learning problems at all. In contrast to previous findings, seizures were not a common feature in our series (only 2 of 17 living probands). Three patients with deletions had cardiac defects and deletion of the KLF13 gene, located in the critical region, may contribute to these abnormalities. The limited data from the single family with the more proximal BP3–BP4 deletion suggest this deletion may have little clinical significance. Patients with duplications of the BP3–BP4–BP5 region did not share a recognisable phenotype, but psychiatric disease was noted in 2 of 4 patients. Conclusions: Overall, our findings broaden the phenotypic spectrum associated with 15q13.3 deletions and suggest that, in some individuals, deletion of 15q13.3 is not sufficient to cause disease. The existence of microdeletion syndromes, associated with an unpredictable and variable phenotypic outcome, will pose the clinician with diagnostic difficulties and challenge the commonly used paradigm in the diagnostic setting that aberrations inherited from a phenotypically normal parent are usually without clinical consequences.


Cell | 2007

A Molecular Pathway Including Id2, Tbx5, and Nkx2-5 Required for Cardiac Conduction System Development

Ivan P. Moskowitz; Jae B. Kim; Meredith L. Moore; Cordula M. Wolf; Michael A. Peterson; Jay Shendure; Marcelo A. Nobrega; Yoshifumi Yokota; Charles I. Berul; Seigo Izumo; Jonathan G. Seidman; Christine E. Seidman

The cardiac conduction system is an anatomically discrete segment of specialized myocardium that initiates and propagates electrical impulses to coordinate myocardial contraction. To define the molecular composition of the mouse ventricular conduction system we used microdissection and transcriptional profiling by serial analysis of gene expression (SAGE). Conduction-system-specific expression for Id2, a member of the Id gene family of transcriptional repressors, was identified. Analyses of Id2-deficient mice demonstrated structural and functional conduction system abnormalities, including left bundle branch block. A 1.2 kb fragment of the Id2 promoter proved sufficient for cooperative regulation by Nkx2-5 and Tbx5 in vitro and for conduction-system-specific gene expression in vivo. Furthermore, compound haploinsufficiency of Tbx5 and Nkx2-5 or Tbx5 and Id2 prevented embryonic specification of the ventricular conduction system. We conclude that a molecular pathway including Tbx5, Nkx2-5, and Id2 coordinates specification of ventricular myocytes into the ventricular conduction system lineage.


Science | 2012

A Fine-Scale Chimpanzee Genetic Map from Population Sequencing

Adam Auton; Adi Fledel-Alon; Susanne P. Pfeifer; Oliver Venn; Laure Ségurel; Teresa Street; Ellen M. Leffler; Rory Bowden; Ivy Aneas; John Broxholme; Peter Humburg; Zamin Iqbal; Gerton Lunter; Julian Maller; Ryan D. Hernandez; Cord Melton; Aarti Venkat; Marcelo A. Nobrega; Ronald E. Bontrop; Simon Myers; Peter Donnelly; Molly Przeworski; Gil McVean

Going Ape Over Genetic Maps Recombination is an important process in generating diversity and producing selectively advantageous genetic combinations. Thus, changes in recombination hotspots may influence speciation. To investigate the variation in recombination processes in humans and their closest existing relatives, Auton et al. (p. 193, published online 15 March) prepared a fine-scale genetic map of the Western chimpanzee and compared it with that of humans. While rates of recombination are comparable between humans and chimpanzees, the locations and genetic motifs associated with recombination differ between the species. Chimpanzees show similar genetic recombination rates as humans but differ in the genomic regions involved. To study the evolution of recombination rates in apes, we developed methodology to construct a fine-scale genetic map from high-throughput sequence data from 10 Western chimpanzees, Pan troglodytes verus. Compared to the human genetic map, broad-scale recombination rates tend to be conserved, but with exceptions, particularly in regions of chromosomal rearrangements and around the site of ancestral fusion in human chromosome 2. At fine scales, chimpanzee recombination is dominated by hotspots, which show no overlap with those of humans even though rates are similarly elevated around CpG islands and decreased within genes. The hotspot-specifying protein PRDM9 shows extensive variation among Western chimpanzees, and there is little evidence that any sequence motifs are enriched in hotspots. The contrasting locations of hotspots provide a natural experiment, which demonstrates the impact of recombination on base composition.


Nature | 2004

Megabase deletions of gene deserts result in viable mice

Marcelo A. Nobrega; Yiwen Zhu; Ingrid Plajzer-Frick; Veena Afzal; Edward M. Rubin

The functional importance of the roughly 98% of mammalian genomes not corresponding to protein coding sequences remains largely undetermined. Here we show that some large-scale deletions of the non-coding DNA referred to as gene deserts can be well tolerated by an organism. We deleted two large non-coding intervals, 1,511 kilobases and 845 kilobases in length, from the mouse genome. Viable mice homozygous for the deletions were generated and were indistinguishable from wild-type littermates with regard to morphology, reproductive fitness, growth, longevity and a variety of parameters assaying general homeostasis. Further detailed analysis of the expression of multiple genes bracketing the deletions revealed only minor expression differences in homozygous deletion and wild-type mice. Together, the two deleted segments harbour 1,243 non-coding sequences conserved between humans and rodents (more than 100 base pairs, 70% identity). Some of the deleted sequences might encode for functions unidentified in our screen; nonetheless, these studies further support the existence of potentially ‘disposable DNA’ in the genomes of mammals.


Genome Research | 2010

An 8q24 gene desert variant associated with prostate cancer risk confers differential in vivo activity to a MYC enhancer

Nora F. Wasserman; Ivy Aneas; Marcelo A. Nobrega

Genome-wide association studies (GWAS) routinely identify risk variants in noncoding DNA, as exemplified by reports of multiple single nucleotide polymorphisms (SNPs) associated with prostate cancer in five independent regions in a gene desert on 8q24. Two of these regions also have been associated with breast and colorectal cancer. These findings implicate functional variation within long-range cis-regulatory elements in disease etiology. We used an in vivo bacterial artificial chromosome (BAC) enhancer-trapping strategy in mice to scan a half-megabase of the 8q24 gene desert encompassing the prostate cancer-associated regions for long-range cis-regulatory elements. These BAC assays identified both prostate and mammary gland enhancer activities within the region. We demonstrate that the 8q24 cancer-associated variant rs6983267 lies within an in vivo prostate enhancer whose expression mimics that of the nearby MYC proto-oncogene. Additionally, we show that the cancer risk allele increases prostate enhancer activity in vivo relative to the non-risk allele. This allele-specific enhancer activity is detectable during early prostate development and throughout prostate maturation, raising the possibility that this SNP could assert its influence on prostate cancer risk before tumorigenesis occurs. Our study represents an efficient strategy to build experimentally on GWAS findings with an in vivo method for rapidly scanning large regions of noncoding DNA for functional cis-regulatory sequences harboring variation implicated in complex diseases.


Genome Research | 2010

Homotypic clusters of transcription factor binding sites are a key component of human promoters and enhancers

Valer Gotea; Axel Visel; John M. Westlund; Marcelo A. Nobrega; Len A. Pennacchio; Ivan Ovcharenko

Clustering of multiple transcription factor binding sites (TFBSs) for the same transcription factor (TF) is a common feature of cis-regulatory modules in invertebrate animals, but the occurrence of such homotypic clusters of TFBSs (HCTs) in the human genome has remained largely unknown. To explore whether HCTs are also common in human and other vertebrates, we used known binding motifs for vertebrate TFs and a hidden Markov model-based approach to detect HCTs in the human, mouse, chicken, and fugu genomes, and examined their association with cis-regulatory modules. We found that evolutionarily conserved HCTs occupy nearly 2% of the human genome, with experimental evidence for individual TFs supporting their binding to predicted HCTs. More than half of the promoters of human genes contain HCTs, with a distribution around the transcription start site in agreement with the experimental data from the ENCODE project. In addition, almost half of the 487 experimentally validated developmental enhancers contain them as well--a number more than 25-fold larger than expected by chance. We also found evidence of negative selection acting on TFBSs within HCTs, as the conservation of TFBSs is stronger than the conservation of sequences separating them. The important role of HCTs as components of developmental enhancers is additionally supported by a strong correlation between HCTs and the binding of the enhancer-associated coactivator protein Ep300 (also known as p300). Experimental validation of HCT-containing elements in both zebrafish and mouse suggest that HCTs could be used to predict both the presence of enhancers and their tissue specificity, and are thus a feature that can be effectively used in deciphering the gene regulatory code. In conclusion, our results indicate that HCTs are a pervasive feature of human cis-regulatory modules and suggest that they play an important role in gene regulation in the human and other vertebrate genomes.

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Ivy Aneas

University of Chicago

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Ivan Ovcharenko

National Institutes of Health

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Howard J. Jacob

Medical College of Wisconsin

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Len A. Pennacchio

Lawrence Berkeley National Laboratory

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Edward M. Rubin

United States Department of Energy

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Gabriela G. Loots

Lawrence Livermore National Laboratory

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