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1.  Heart genetics in a small package, exploiting the condensed genome of Ciona intestinalis 
Defects in the initial establishment of cardiogenic cell fate are likely to contribute to pervasive human congenital cardiac abnormalities. However, the molecular underpinnings of nascent cardiac fate induction have proven difficult to decipher. In this review we explore the participation of extracellular, cellular and nuclear factors in comprehensive specification networks. At each level, we elaborate on insights gained through the study of cardiogenesis in the invertebrate chordate Ciona intestinalis and propose productive lines of future research. In-depth discussion of pre-cardiac induction is intended to serve as a paradigm, illustrating the potential use of Ciona to elucidate comprehensive networks underlying additional aspects of chordate cardiogenesis, including directed migration and subspecification of cardiac and pharyngeal lineages.
PMCID: PMC3896895  PMID: 24005910
Mesp; FGF; gene regulatory networks; extracellular matrix; cardiac induction; chordate evolution
2.  Epigenetic mechanisms and developmental choice hierarchies in T-lymphocyte development 
Briefings in Functional Genomics  2013;12(6):512-524.
Three interlocking problems in gene regulation are: how to explain genome-wide targeting of transcription factors in different cell types, how prior transcription factor action can establish an ‘epigenetic state’ that changes the options for future transcription factor action, and how directly a sequence of developmental decisions can be memorialized in a hierarchy of repression structures applied to key genes of the ‘paths not taken’. This review uses the finely staged process of T-cell lineage commitment as a test case in which to examine how changes in developmental status are reflected in changes in transcription factor expression, transcription factor binding distribution across genomic sites, and chromatin modification. These are evaluated in a framework of reciprocal effects of previous chromatin structure features on transcription factor access and of transcription factor binding on other factors and on future chromatin structure.
PMCID: PMC3838197  PMID: 23922132
DNA binding; histone methylation; DNA methylation; lineage commitment; repression; hematopoiesis
3.  Fungal cellulose degradation by oxidative enzymes: from dysfunctional GH61 family to powerful lytic polysaccharide monooxygenase family 
Briefings in Functional Genomics  2014;13(6):471-481.
Our understanding of fungal cellulose degradation has shifted dramatically in the past few years with the characterization of a new class of secreted enzymes, the lytic polysaccharide monooxygenases (LPMO). After a period of intense research covering structural, biochemical, theoretical and evolutionary aspects, we have a picture of them as wedge-like copper-dependent metalloenzymes that on reduction generate a radical copper-oxyl species, which cleaves mainly crystalline cellulose. The main biological function lies in the synergism of fungal LPMOs with canonical hydrolytic cellulases in achieving efficient cellulose degradation. Their important role in cellulose degradation is highlighted by the wide distribution and often numerous occurrences in the genomes of almost all plant cell-wall degrading fungi. In this review, we provide an overview of the latest achievements in LPMO research and consider the open questions and challenges that undoubtedly will continue to stimulate interest in this new and exciting group of enzymes.
PMCID: PMC4239789  PMID: 25217478
AA9; GH61; cellobiose dehydrogenase; oxidative cellulose degradation
4.  Genomic approaches in breast cancer research 
Briefings in Functional Genomics  2013;12(5):391-396.
Microarray technologies provide high-throughput analysis of genes that are differentially expressed in humans and other species, and thereby provide a means to measure how biological systems are altered during development or disease states. Within, we review how high-throughput genomic technologies have increased our understanding about the molecular complexity of breast cancer, identified distinct molecular phenotypes and how they can be used to increase the accuracy of predicted clinical outcome.
PMCID: PMC3776566  PMID: 23788797
breast cancer; microarray; genomics; tumor; histology
5.  Using population isolates in genetic association studies 
Briefings in Functional Genomics  2014;13(5):371-377.
The use of genetically isolated populations can empower next-generation association studies. In this review, we discuss the advantages of this approach and review study design and analytical considerations of genetic association studies focusing on isolates. We cite successful examples of using population isolates in association studies and outline potential ways forward.
PMCID: PMC4168662  PMID: 25009120
isolated populations; rare variants; complex disease; genetic association studies
6.  Methodology for the analysis of rare genetic variation in genome-wide association and re-sequencing studies of complex human traits 
Briefings in Functional Genomics  2014;13(5):362-370.
Genome-wide association studies have been successful in identifying common variants that impact complex human traits and diseases. However, despite this success, the joint effects of these variants explain only a small proportion of the genetic variance in these phenotypes, leading to speculation that rare genetic variation might account for much of the ‘missing heritability’. Consequently, there has been an exciting period of research and development into the methodology for the analysis of rare genetic variants, typically by considering their joint effects on complex traits within the same functional unit or genomic region. In this review, we describe a general framework for modelling the joint effects of rare genetic variants on complex traits in association studies of unrelated individuals. We summarise a range of widely used association tests that have been developed from this model and provide an overview of the relative performance of these approaches from published simulation studies.
PMCID: PMC4168660  PMID: 24916163
rare variant; burden test; dispersion test; statistical methodology; genome-wide association; whole-genome and whole-exome re-sequencing
7.  Structural variations in plant genomes 
Briefings in Functional Genomics  2014;13(4):296-307.
Differences between plant genomes range from single nucleotide polymorphisms to large-scale duplications, deletions and rearrangements. The large polymorphisms are termed structural variants (SVs). SVs have received significant attention in human genetics and were found to be responsible for various chronic diseases. However, little effort has been directed towards understanding the role of SVs in plants. Many recent advances in plant genetics have resulted from improvements in high-resolution technologies for measuring SVs, including microarray-based techniques, and more recently, high-throughput DNA sequencing. In this review we describe recent reports of SV in plants and describe the genomic technologies currently used to measure these SVs.
PMCID: PMC4110416  PMID: 24907366
structural variations (SVs); next-generation sequencing (NGS); copy number variations (CNVs); presence and absence variations (PAVs); inversions; translocations
8.  TAL effectors: tools for DNA Targeting 
Briefings in Functional Genomics  2014;13(5):409-419.
Xanthomonas phytopathogenic bacteria produce unique transcription activator-like effector (TALE) proteins that recognize and activate specific plant promoters through a set of tandem repeats. A unique TALE-DNA-binding code uses two polymorphic amino acids in each repeat to mediate recognition of specific nucleotides. The order of repeats determines effector’s specificity toward the cognate nucleotide sequence of the sense DNA strand. Artificially designed TALE-DNA-binding domains fused to nuclease or activation and repressor domains provide an outstanding toolbox for targeted gene editing and gene regulation in research, biotechnology and gene therapy. Gene editing with custom-designed TALE nucleases (TALENs) extends the repertoire of targeted genome modifications across a broad spectrum of organisms ranging from plants and insect to mammals.
PMCID: PMC4168661  PMID: 24907364
TALE; TALEN; ZFN; FokI; DNA editing
9.  The impact of linked selection on plant genomic variation 
Briefings in Functional Genomics  2014;13(4):268-275.
Understanding the forces that shape patterns of genetic variation across the genome is a major aim in evolutionary genetics. An emerging insight from analyses of genome-wide polymorphism and divergence data is that selection on linked sites can have an important impact on neutral genetic variation. However, in contrast to Drosophila, which exhibits a signature of recurrent hitchhiking, many plant genomes studied so far seem to mainly be affected by background selection. Moreover, many plants do not exhibit classic signatures of linked selection, such as a correlation between recombination rate and neutral diversity. In this review, I discuss the impact of genome architecture and mating system on the expected signature of linked selection in plants and review empirical evidence for linked selection, with a focus on plant model systems. Finally, I discuss the implications of linked selection for inference of demographic history in plants.
PMCID: PMC4110415  PMID: 24759704
hitchhiking; genetic draft; recombination rate; genome size; FST; demographic inference
10.  Turning single cells into microarrays by super-resolution barcoding 
In this review, we discuss a strategy to bring genomics and proteomics into single cells by super-resolution microscopy. The basis for this new approach are the following: given the 10 nm resolution of a super-resolution microscope and a typical cell with a size of (10 µm)3, individual cells contain effectively 109 super-resolution pixels or bits of information. Most eukaryotic cells have 104 genes and cellular abundances of 10–100 copies per transcript. Thus, under a super-resolution microscope, an individual cell has 1000 times more pixel volume or information capacities than is needed to encode all transcripts within that cell. Individual species of mRNA can be uniquely identified by labeling them each with a distinct combination of fluorophores by fluorescence in situ hybridization. With at least 15 fluorophores available in super-resolution, hundreds of genes in can be barcoded with a three-color barcode (3C15 = 455). These calculations suggest that by combining super-resolution microscopy and barcode labeling, single cells can be turned into informatics platforms denser than microarrays and that molecular species in individual cells can be profiled in a massively parallel fashion.
PMCID: PMC3609437  PMID: 23178478
super-resolution microscopy; systems biology; single cells; single-molecule FISH
11.  Dynamics of the DNA damage response: insights from live-cell imaging 
Briefings in Functional Genomics  2013;12(2):109-117.
All organisms have to safeguard the integrity of their genome to prevent malfunctioning and oncogenic transformation. Sophisticated DNA damage response mechanisms have evolved to detect and repair genomic lesions. With the emergence of live-cell microscopy of individual cells, we now begin to appreciate the complex spatiotemporal kinetics of the DNA damage response and can address the causes and consequences of the heterogeneity in the responses of genetically identical cells. Here, we highlight key discoveries where live-cell imaging has provided unprecedented insights into how cells respond to DNA double-strand breaks and discuss the main challenges and promises in using this technique.
PMCID: PMC3609438  PMID: 23292635
live-cell imaging; single cell; DNA damage; fluorescence microscopy; dynamics
12.  Restoring totipotency through epigenetic reprogramming 
Briefings in Functional Genomics  2012;12(2):118-128.
Epigenetic modifications are implicated in the maintenance and regulation of transcriptional memory by marking genes that were previously transcribed to facilitate transmission of these expression patterns through cell division. During germline specification and maintenance, extensive epigenetic modifications are acquired. Yet somehow at fertilization, the fusion of the highly differentiated sperm and egg results in formation of the totipotent zygote. This massive change in cell fate implies that the selective erasure and maintenance of epigenetic modifications at fertilization may be critical for the re-establishment of totipotency. In this review, we discuss recent studies that provide insight into the extensive epigenetic reprogramming that occurs around fertilization and the mechanisms that may be involved in the re-establishment of totipotency in the embryo.
PMCID: PMC4023274  PMID: 23117862
13.  Epigenomics and the concept of degeneracy in biological systems 
Briefings in Functional Genomics  2013;13(3):191-202.
Researchers in the field of epigenomics are developing more nuanced understandings of biological complexity, and exploring the multiple pathways that lead to phenotypic expression. The concept of degeneracy—referring to the multiple pathways that a system recruits to achieve functional plasticity—is an important conceptual accompaniment to the growing body of knowledge in epigenomics. Distinct from degradation, redundancy and dilapidation; degeneracy refers to the plasticity of traits whose function overlaps in some environments, but diverges in others. While a redundant system is composed of repeated identical elements performing the same function, a degenerate system is composed of different elements performing similar or overlapping functions. Here, we describe the degenerate structure of gene regulatory systems from the basic genetic code to flexible epigenomic modifications, and discuss how these structural features have contributed to organism complexity, robustness, plasticity and evolvability.
PMCID: PMC4031454  PMID: 24335757
epigenetic code; pluripotentiality; robustness; redundancy; DNA methylation; histone modifications; social insect; honey bee
14.  C. elegans epigenetic regulation in development and aging 
Briefings in Functional Genomics  2013;13(3):223-234.
The precise developmental map of the Caenorhabditis elegans cell lineage, as well as a complete genome sequence and feasibility of genetic manipulation make this nematode species highly attractive to study the role of epigenetics during development. Genetic dissection of phenotypical traits, such as formation of egg-laying organs or starvation-resistant dauer larvae, has illustrated how chromatin modifiers may regulate specific cell-fate decisions and behavioral programs. Moreover, the transparent body of C. elegans facilitates non-invasive microscopy to study tissue-specific accumulation of heterochromatin at the nuclear periphery. We also review here recent findings on how small RNA molecules contribute to epigenetic control of gene expression that can be propagated for several generations and eventually determine longevity.
PMCID: PMC4031453  PMID: 24326118
Caenorhabditis elegans; chromatin organization; longevity; organogenesis; small RNA; transcriptional silencing
15.  Advances in genomics of bony fish 
Briefings in Functional Genomics  2013;13(2):144-156.
In this review, we present an overview of the recent advances of genomic technologies applied to studies of fish species belonging to the superclass of Osteichthyes (bony fish) with a major emphasis on the infraclass of Teleostei, also called teleosts. This superclass that represents more than 50% of all known vertebrate species has gained considerable attention from genome researchers in the last decade. We discuss many examples that demonstrate that this highly deserved attention is currently leading to new opportunities for answering important biological questions on gene function and evolutionary processes. In addition to giving an overview of the technologies that have been applied for studying various fish species we put the recent advances in genome research on the model species zebrafish and medaka in the context of its impact for studies of all fish of the superclass of Osteichthyes. We thereby want to illustrate how the combined value of research on model species together with a broad angle perspective on all bony fish species will have a huge impact on research in all fields of fundamental science and will speed up applications in many societally important areas such as the development of new medicines, toxicology test systems, environmental sensing systems and sustainable aquaculture strategies.
PMCID: PMC3954040  PMID: 24291769
fish models; teleosts; genomics; aquaculture; next-generation sequencing; zebrafish; medaka
16.  Zebrafish sex: a complicated affair 
Briefings in Functional Genomics  2013;13(2):172-187.
In this review, we provide a detailed overview of studies on the elusive sex determination (SD) and gonad differentiation mechanisms of zebrafish (Danio rerio). We show that the data obtained from most studies are compatible with polygenic sex determination (PSD), where the decision is made by the allelic combinations of several loci. These loci are typically dispersed throughout the genome, but in some teleost species a few of them might be located on a preferential pair of (sex) chromosomes. The PSD system has a much higher level of variation of SD genotypes both at the level of gametes and the sexual genotype of individuals, than that of the chromosomal sex determination systems. The early sexual development of zebrafish males is a complicated process, as they first develop a ‘juvenile ovary’, that later undergoes a transformation to give way to a testis. To date, three major developmental pathways were shown to be involved with gonad differentiation through the modulation of programmed cell death. In our opinion, there are more pathways participating in the regulation of zebrafish gonad differentiation/transformation. Introduction of additional powerful large-scale genomic approaches into the analysis of zebrafish reproduction will result in further deepening of our knowledge as well as identification of additional pathways and genes associated with these processes in the near future.
PMCID: PMC3954038  PMID: 24148942
polygenic sex determination; sex chromosome; gonad differentiation; teleost; fish; Danio rerio
17.  From a gene-centric to whole-proteome view of differentiation of T helper cell subsets 
Briefings in Functional Genomics  2013;12(6):471-482.
Proper differentiation of naïve T helper cells into functionally distinct subsets is of critical importance to human health. Consequently, the process is tightly controlled by a complex intracellular signalling network. To dissect the regulatory principles of this network, immunologists have early on embraced system-wide transcriptomics tools, leading to identification of large panels of potential regulatory factors. In contrast, the use of proteomics approaches in T helper cell research has been notably rare, and to this date relatively few high-throughput datasets have been reported. Here, we discuss the importance of such research and envision the possibilities afforded by mass spectrometry-based proteomics in the near future.
PMCID: PMC3838199  PMID: 24106101
T helper cell; systems biology; proteomics; mass spectrometry; transcriptomics; T cell activation
18.  Genomics of sex determination in Drosophila 
Briefings in Functional Genomics  2012;11(5):387-394.
Drosophilists have identified many, or perhaps most, of the key regulatory genes determining sex using classical genetics, however, regulatory genes must ultimately result in the deployment of the genome in a quantitative manner, replete with complex interactions with other regulatory pathways. In the last decade, genomics has provided a rich picture of the transcriptional profile of the sexes that underlies sexual dimorphism. The current challenge is linking transcriptional profiles with the regulatory genes. This will be a complex synthesis, but the prospects for progress are outstanding.
PMCID: PMC3459014  PMID: 23023665
drosophila; transcriptome; sex determination; effector; selector
19.  Interpreting the regulatory genome: the genomics of transcription factor function in Drosophila melanogaster 
Briefings in Functional Genomics  2012;11(5):336-346.
Researchers have now had access to the fully sequenced Drosophila melanogaster genome for over a decade, and the sequenced genomes of 11 additional Drosophila species have been available for almost 5 years, with more species’ genomes becoming available every year [Adams MD, Celniker SE, Holt RA, et al. The genome sequence of Drosophila melanogaster. Science 2000;287:2185–95; Clark AG, Eisen MB, Smith DR, et al. Evolution of genes and genomes on the Drosophila phylogeny. Nature 2007;450:203–18]. Although the best studied of the D. melanogaster transcription factors (TFs) were cloned before sequencing of the genome, the availability of sequence data promised to transform our understanding of TFs and gene regulatory networks. Sequenced genomes have allowed researchers to generate tools for high-throughput characterization of gene expression levels, genome-wide TF localization and analyses of evolutionary constraints on DNA elements across multiple species. With an estimated 700 DNA-binding proteins in the Drosophila genome, it will be many years before each potential sequence-specific TF is studied in detail, yet the last decade of functional genomics research has already impacted our view of gene regulatory networks and TF DNA recognition.
PMCID: PMC3459015  PMID: 23023663
Drosophila; transcription factor; genomics; enhancer; Zelda
20.  Regulatory RNAs in the light of Drosophila genomics 
Briefings in Functional Genomics  2012;11(5):356-365.
Many aspects of gene regulation are mediated by RNA molecules. However, regulatory RNAs have remained elusive until very recently. At least three types of small regulatory RNAs have been characterized in Drosophila: microRNAs (miRNAs), piwi-interacting RNAs and endogenous siRNAs. A fourth class of regulatory RNAs includes known long non-coding RNAs such as roX1 or bxd. The initial sequencing of the Drosophila melanogaster genome has served as a scaffold to study the transcriptional profile of an animal, revealing the complexities of the function and biogenesis of regulatory RNAs. The comparative analysis of 12 Drosophila genomes has been crucial for the study of microRNA evolution. However, comparative genomics of other RNA regulators is confounded by technical problems: genomic loci are poorly conserved and frequently encoded in the heterochromatin. Future developments in genome sequencing and population genomics in Drosophila will continue to shed light on the conservation, evolution and function of regulatory RNAs.
PMCID: PMC4007103  PMID: 22956639
Non-coding RNA; miRNA; piRNA; siRNA; transposable elements; gene regulation
21.  The IL-10/STAT3-mediated anti-inflammatory response: recent developments and future challenges 
Briefings in Functional Genomics  2013;12(6):489-498.
Inflammation is a fundamental response of the immune system whose successful termination involves the elimination of the invading pathogens, the resolution of inflammation and the repair of the local damaged tissue. In this context, the interleukin 10 (IL-10)-mediated anti-inflammatory response (AIR) represents an essential homeostatic mechanism that controls the degree and duration of inflammation. Here, we review recent work on the mechanistic characterization of the IL-10-mediated AIR on multiple levels: from the cataloguing of the in vivo genomic targets of STAT3 (the transcription factor downstream of IL-10) to the identification of specific co-factors that endow STAT3 with genomic-binding specificity, and how genomic and computational methods are being used to elucidate the regulatory mechanisms of this essential physiological response in macrophages.
PMCID: PMC3838198  PMID: 23943603
IL-10; JAK1; STAT3; anti-inflammatory response; macrophages; transcriptional regulatory modules; bioinformatics
22.  Transcription factor interplay in T helper cell differentiation 
Briefings in Functional Genomics  2013;12(6):499-511.
The differentiation of CD4 helper T cells into specialized effector lineages has provided a powerful model for understanding immune cell differentiation. Distinct lineages have been defined by differential expression of signature cytokines and the lineage-specifying transcription factors necessary and sufficient for their production. The traditional paradigm of differentiation towards Th1 and Th2 subtypes driven by T-bet and GATA3, respectively, has been extended to incorporate additional T cell lineages and transcriptional regulators. Technological advances have expanded our view of these lineage-specifying transcription factors to the whole genome and revealed unexpected interplay between them. From these data, it is becoming clear that lineage specification is more complex and plastic than previous models might have suggested. Here, we present an overview of the different forms of transcription factor interplay that have been identified and how T cell phenotypes arise as a product of this interplay within complex regulatory networks. We also suggest experimental strategies that will provide further insight into the mechanisms that underlie T cell lineage specification and plasticity.
PMCID: PMC3838196  PMID: 23878131
T cell; transcription factor; lineage-specification; cell differentiation; plasticity; enhancer
23.  Functional genomics of Plasmodium falciparum using metabolic modelling and analysis 
Briefings in Functional Genomics  2013;12(4):316-327.
Plasmodium falciparum is an obligate intracellular parasite and the leading cause of severe malaria responsible for tremendous morbidity and mortality particularly in sub-Saharan Africa. Successful completion of the P. falciparum genome sequencing project in 2002 provided a comprehensive foundation for functional genomic studies on this pathogen in the following decade. Over this period, a large spectrum of experimental approaches has been deployed to improve and expand the scope of functionally annotated genes. Meanwhile, rapidly evolving methods of systems biology have also begun to contribute to a more global understanding of various aspects of the biology and pathogenesis of malaria. Herein we provide an overview on metabolic modelling, which has the capability to integrate information from functional genomics studies in P. falciparum and guide future malaria research efforts towards the identification of novel candidate drug targets.
PMCID: PMC3743259  PMID: 23793264
Plasmodium falciparum; central carbon metabolism; systems biology; flux-balance analysis; constraint-based modelling; in silico gene essentiality
24.  WRAD: enabler of the SET1-family of H3K4 methyltransferases 
Briefings in Functional Genomics  2012;11(3):217-226.
Methylation of histone H3 at lysine 4 (H3K4) is a conserved feature of active chromatin catalyzed by methyltransferases of the SET1-family (SET1A, SET1B, MLL1, MLL2, MLL3 and MLL4 in humans). These enzymes participate in diverse gene regulatory networks with a multitude of known biological functions, including direct involvement in several human disease states. Unlike most lysine methyltransferases, SET1-family enzymes are only fully active in the context of a multi-subunit complex, which includes a protein module comprised of WDR5, RbBP5, ASH2L and DPY-30 (WRAD). These proteins bind in close proximity to the catalytic SET domain of SET1-family enzymes and stimulate H3K4 methyltransferase activity. The mechanism by which WRAD promotes catalysis involves elements of allosteric control and possibly the utilization of a second H3K4 methyltransferase active site present within WRAD itself. WRAD components also engage in physical interactions that recruit SET1-family proteins to target sites on chromatin. Here, the known molecular mechanisms through which WRAD enables the function of SET1-related enzymes will be reviewed.
PMCID: PMC3388306  PMID: 22652693
25.  TET proteins: on the frenetic hunt for new cytosine modifications 
Briefings in Functional Genomics  2013;12(3):191-204.
Epigenetic genome marking and chromatin regulation are central to establishing tissue-specific gene expression programs, and hence to several biological processes. Until recently, the only known epigenetic mark on DNA in mammals was 5-methylcytosine, established and propagated by DNA methyltransferases and generally associated with gene repression. All of a sudden, a host of new actors—novel cytosine modifications and the ten eleven translocation (TET) enzymes—has appeared on the scene, sparking great interest. The challenge is now to uncover the roles they play and how they relate to DNA demethylation. Knowledge is accumulating at a frantic pace, linking these new players to essential biological processes (e.g. cell pluripotency and development) and also to cancerogenesis. Here, we review the recent progress in this exciting field, highlighting the TET enzymes as epigenetic DNA modifiers, their physiological roles, and their functions in health and disease. We also discuss the need to find relevant TET interactants and the newly discovered TET–O-linked N-acetylglucosamine transferase (OGT) pathway.
PMCID: PMC3662890  PMID: 23625996
epigenetics; DNA methylation; hydroxymethylation; TET proteins; OGT

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