Publications by authors named "Lisa Stubbs"

48 Publications

Site-Specific Phosphorylation of Histone H1.4 Is Associated with Transcription Activation.

Int J Mol Sci 2020 Nov 23;21(22). Epub 2020 Nov 23.

Department of Cell and Developmental Biology, School of Molecular and Cellular Biology, University of Illinois at Urbana Champaign, B107 Chemistry and Life Science Building, MC-123, 601 S. Goodwin Ave., Urbana, IL 61801, USA.

Core histone variants, such as H2A.X and H3.3, serve specialized roles in chromatin processes that depend on the genomic distributions and amino acid sequence differences of the variant proteins. Modifications of these variants alter interactions with other chromatin components and thus the protein's functions. These inferences add to the growing arsenal of evidence against the older generic view of those linker histones as redundant repressors. Furthermore, certain modifications of specific H1 variants can confer distinct roles. On the one hand, it has been reported that the phosphorylation of H1 results in its release from chromatin and the subsequent transcription of HIV-1 genes. On the other hand, recent evidence indicates that phosphorylated H1 may in fact be associated with active promoters. This conflict suggests that different H1 isoforms and modified versions of these variants are not redundant when together but may play distinct functional roles. Here, we provide the first genome-wide evidence that when phosphorylated, the H1.4 variant remains associated with active promoters and may even play a role in transcription activation. Using novel, highly specific antibodies, we generated the first genome-wide view of the H1.4 isoform phosphorylated at serine 187 (pS187-H1.4) in estradiol-inducible MCF7 cells. We observe that pS187-H1.4 is enriched primarily at the transcription start sites (TSSs) of genes activated by estradiol treatment and depleted from those that are repressed. We also show that pS187-H1.4 associates with 'early estrogen response' genes and stably interacts with RNAPII. Based on the observations presented here, we propose that phosphorylation at S187 by CDK9 represents an early event required for gene activation. This event may also be involved in the release of promoter-proximal polymerases to begin elongation by interacting directly with the polymerase or other parts of the transcription machinery. Although we focused on estrogen-responsive genes, taking into account previous evidence of H1.4's enrichment of promoters of pluripotency genes, and its involvement with rDNA activation, we propose that H1.4 phosphorylation for gene activation may be a more global observation.
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http://dx.doi.org/10.3390/ijms21228861DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7700352PMC
November 2020

Behavior-related gene regulatory networks: A new level of organization in the brain.

Proc Natl Acad Sci U S A 2020 09 13;117(38):23270-23279. Epub 2020 Jul 13.

Carl R. Woese Institute for Genomic Biology, University of Illinois, Urbana-Champaign, IL 61801;

Neuronal networks are the standard heuristic model today for describing brain activity associated with animal behavior. Recent studies have revealed an extensive role for a completely distinct layer of networked activities in the brain-the gene regulatory network (GRN)-that orchestrates expression levels of hundreds to thousands of genes in a behavior-related manner. We examine emerging insights into the relationships between these two types of networks and discuss their interplay in spatial as well as temporal dimensions, across multiple scales of organization. We discuss properties expected of behavior-related GRNs by drawing inspiration from the rich literature on GRNs related to animal development, comparing and contrasting these two broad classes of GRNs as they relate to their respective phenotypic manifestations. Developmental GRNs also represent a third layer of network biology, playing out over a third timescale, which is believed to play a crucial mediatory role between neuronal networks and behavioral GRNs. We end with a special emphasis on social behavior, discuss whether unique GRN organization and -regulatory architecture underlies this special class of behavior, and review literature that suggests an affirmative answer.
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http://dx.doi.org/10.1073/pnas.1921625117DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7519311PMC
September 2020

Allele-specific enhancer interaction at the Peg3 imprinted domain.

PLoS One 2019 22;14(10):e0224287. Epub 2019 Oct 22.

Cell and Developmental Biology, Institute for Genomic Biology, University of Illinois, Urbana, Illinois, United States of America.

The parental allele specificity of mammalian imprinted genes has been evolutionarily well conserved, although its functional constraints and associated mechanisms are not fully understood. In the current study, we generated a mouse mutant with switched active alleles driving the switch from paternal-to-maternal expression for Peg3 and the maternal-to-paternal expression for Zim1. The expression levels of Peg3 and Zim1, but not the spatial expression patterns, within the brain showed clear differences between wild type and mutant animals. We identified putative enhancers localized upstream of Peg3 that displayed allele-biased DNA methylation, and that also participate in allele-biased chromosomal conformations with regional promoters. Most importantly, these data suggest for the first time that long-distance enhancers may contribute to allelic expression within imprinted domains through allele-biased interactions with regional promoters.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0224287PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6804975PMC
March 2020

A Mouse Mutation That Dysregulates Neighboring and Genes Is Associated with Phenotypes Related to the Human AUTS2 Syndrome.

G3 (Bethesda) 2019 11 5;9(11):3891-3906. Epub 2019 Nov 5.

Carl R. Woese Institute for Genomic Biology,

was originally discovered as the gene disrupted by a translocation in human twins with Autism spectrum disorder, intellectual disability, and epilepsy. Since that initial finding, -linked mutations and variants have been associated with a very broad array of neuropsychiatric disorders, sugg esting that is required for fundamental steps of neurodevelopment. However, genotype-phenotype correlations in this region are complicated, because most mutations could also involve neighboring genes. Of particular interest is the nearest downstream neighbor of , , which encodes a brain-expressed N-acetylgalactosaminyltransferase of unknown brain function. Here we describe a mouse () mutation, T(5G2;8A1)GSO (abbreviated 16Gso), a reciprocal translocation that breaks between and and dysregulates both genes. Despite this complex regulatory effect, 16Gso homozygotes model certain human -linked phenotypes very well. In addition to abnormalities in growth, craniofacial structure, learning and memory, and behavior, 16Gso homozygotes display distinct pathologies of the cerebellum and hippocampus that are similar to those associated with autism and other types of -linked neurological disease. Analyzing mutant cerebellar and hippocampal transcriptomes to explain this pathology, we identified disturbances in pathways related to neuron and synapse maturation, neurotransmitter signaling, and cellular stress, suggesting possible cellular mechanisms. These pathways, coupled with the translocation's selective effects on isoforms and coordinated dysregulation of , suggest novel hypotheses regarding the etiology of the human "AUTS2 syndrome" and the wide array of neurodevelopmental disorders linked to variance in this genomic region.
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http://dx.doi.org/10.1534/g3.119.400723DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6829118PMC
November 2019

An extended regulatory landscape drives Tbx18 activity in a variety of prostate-associated cell lineages.

Dev Biol 2019 02 27;446(2):180-192. Epub 2018 Dec 27.

Department of Cell and Developmental Biology, University of Illinois, Urbana-Champaign, United States. Electronic address:

The evolutionarily conserved transcription factor, Tbx18, is expressed in a dynamic pattern throughout embryonic and early postnatal life and plays crucial roles in the development of multiple organ systems. Previous studies have indicated that this dynamic function is controlled by an expansive regulatory structure, extending far upstream and downstream of the gene. With the goal of identifying elements that interact with the Tbx18 promoter in developing prostate, we coupled chromatin conformation capture (4C) and ATAC-seq from embryonic day 18.5 (E18.5) mouse urogenital sinus (UGS), where Tbx18 is highly expressed. The data revealed dozens of active chromatin elements distributed throughout a 1.5 million base pair topologically associating domain (TAD). To identify cell types contributing to this chromatin signal, we used lineage tracing methods with a Tbx18 Cre "knock-in" allele; these data show clearly that Tbx18-expressing precursors differentiate into wide array of cell types in multiple tissue compartments, most of which have not been previously reported. We also used a 209 kb Cre-expressing Tbx18 transgene, to partition enhancers for specific precursor types into two rough spatial domains. Within this central 209 kb compartment, we identified ECR1, previously described to regulate Tbx18 expression in ureter, as an active regulator of UGS expression. Together these data define the diverse fates of Tbx18+ precursors in prostate-associated tissues for the first time, and identify a highly active TAD controlling the gene's essential function in this tissue.
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http://dx.doi.org/10.1016/j.ydbio.2018.11.023DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6368454PMC
February 2019

Honey bee neurogenomic responses to affiliative and agonistic social interactions.

Genes Brain Behav 2019 01 4;18(1):e12509. Epub 2018 Sep 4.

Carl R. Woese Institute for Genomic Biology, University of Illinois at Urbana-Champaign (UIUC), Urbana, Illinois.

Social interactions can be divided into two categories, affiliative and agonistic. How neurogenomic responses reflect these opposing valences is a central question in the biological embedding of experience. To address this question, we exposed honey bees to a queen larva, which evokes nursing, an affiliative alloparenting interaction, and measured the transcriptomic response of the mushroom body brain region at different times after exposure. Hundreds of genes were differentially expressed at distinct time points, revealing a dynamic temporal patterning of the response. Comparing these results to our previously published research on agonistic aggressive interactions, we found both shared and unique transcriptomic responses to each interaction. The commonly responding gene set was enriched for nuclear receptor signaling, the set specific to nursing was enriched for olfaction and neuron differentiation, and the set enriched for aggression was enriched for cytoskeleton, metabolism, and chromosome organization. Whole brain histone profiling after the affiliative interaction revealed few changes in chromatin accessibility, suggesting that the transcriptomic changes derive from already accessible areas of the genome. Although only one stimulus of each type was studied, we suggest that elements of the observed transcriptomic responses reflect molecular encoding of stimulus valence, thus priming individuals for future encounters. This hypothesis is supported by behavioral analyses showing that bees responding to either the affiliative or agonistic stimulus exhibited a higher probability of repeating the same behavior but a lower probability of performing the opposite behavior. These findings add to our understanding of the biological embedding at the molecular level.
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http://dx.doi.org/10.1111/gbb.12509DOI Listing
January 2019

Cross-species systems analysis of evolutionary toolkits of neurogenomic response to social challenge.

Genes Brain Behav 2019 01 16;18(1):e12502. Epub 2018 Jul 16.

Carl R. Woese Institute for Genomic Biology, University of Illinois at Urbana-Champaign, Urbana, Illinois.

Social challenges like territorial intrusions evoke behavioral responses in widely diverging species. Recent work has showed that evolutionary "toolkits"-genes and modules with lineage-specific variations but deep conservation of function-participate in the behavioral response to social challenge. Here, we develop a multispecies computational-experimental approach to characterize such a toolkit at a systems level. Brain transcriptomic responses to social challenge was probed via RNA-seq profiling in three diverged species-honey bees, mice and three-spined stickleback fish-following a common methodology, allowing fair comparisons across species. Data were collected from multiple brain regions and multiple time points after social challenge exposure, achieving anatomical and temporal resolution substantially greater than previous work. We developed statistically rigorous analyses equipped to find homologous functional groups among these species at the levels of individual genes, functional and coexpressed gene modules, and transcription factor subnetworks. We identified six orthogroups involved in response to social challenge, including groups represented by mouse genes Npas4 and Nr4a1, as well as common modulation of systems such as transcriptional regulators, ion channels, G-protein-coupled receptors and synaptic proteins. We also identified conserved coexpression modules enriched for mitochondrial fatty acid metabolism and heat shock that constitute the shared neurogenomic response. Our analysis suggests a toolkit wherein nuclear receptors, interacting with chaperones, induce transcriptional changes in mitochondrial activity, neural cytoarchitecture and synaptic transmission after social challenge. It shows systems-level mechanisms that have been repeatedly co-opted during evolution of analogous behaviors, thus advancing the genetic toolkit concept beyond individual genes.
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http://dx.doi.org/10.1111/gbb.12502DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6314924PMC
January 2019

Comparative analysis of weighted gene co-expression networks in human and mouse.

PLoS One 2017 21;12(11):e0187611. Epub 2017 Nov 21.

Department of Biotechnology, NTNU - Norwegian University of Science and Technology, N-7491 Trondheim, Norway.

The application of complex network modeling to analyze large co-expression data sets has gained traction during the last decade. In particular, the use of the weighted gene co-expression network analysis framework has allowed an unbiased and systems-level investigation of genotype-phenotype relationships in a wide range of systems. Since mouse is an important model organism for biomedical research on human disease, it is of great interest to identify similarities and differences in the functional roles of human and mouse orthologous genes. Here, we develop a novel network comparison approach which we demonstrate by comparing two gene-expression data sets from a large number of human and mouse tissues. The method uses weighted topological overlap alongside the recently developed network-decomposition method of s-core analysis, which is suitable for making gene-centrality rankings for weighted networks. The aim is to identify globally central genes separately in the human and mouse networks. By comparing the ranked gene lists, we identify genes that display conserved or diverged centrality-characteristics across the networks. This framework only assumes a single threshold value that is chosen from a statistical analysis, and it may be applied to arbitrary network structures and edge-weight distributions, also outside the context of biology. When conducting the comparative network analysis, both within and across the two species, we find a clear pattern of enrichment of transcription factors, for the homeobox domain in particular, among the globally central genes. We also perform gene-ontology term enrichment analysis and look at disease-related genes for the separate networks as well as the network comparisons. We find that gene ontology terms related to regulation and development are generally enriched across the networks. In particular, the genes FOXE3, RHO, RUNX2, ALX3 and RARA, which are disease genes in either human or mouse, are on the top-10 list of globally central genes in the human and mouse networks.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0187611PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5697817PMC
December 2017

Temporal dynamics of neurogenomic plasticity in response to social interactions in male threespined sticklebacks.

PLoS Genet 2017 Jul 13;13(7):e1006840. Epub 2017 Jul 13.

Carl R. Woese Institute for Genomic Biology, University of Illinois, Urbana Champaign, Urbana, IL, United States of America.

Animals exhibit dramatic immediate behavioral plasticity in response to social interactions, and brief social interactions can shape the future social landscape. However, the molecular mechanisms contributing to behavioral plasticity are unclear. Here, we show that the genome dynamically responds to social interactions with multiple waves of transcription associated with distinct molecular functions in the brain of male threespined sticklebacks, a species famous for its behavioral repertoire and evolution. Some biological functions (e.g., hormone activity) peaked soon after a brief territorial challenge and then declined, while others (e.g., immune response) peaked hours afterwards. We identify transcription factors that are predicted to coordinate waves of transcription associated with different components of behavioral plasticity. Next, using H3K27Ac as a marker of chromatin accessibility, we show that a brief territorial intrusion was sufficient to cause rapid and dramatic changes in the epigenome. Finally, we integrate the time course brain gene expression data with a transcriptional regulatory network, and link gene expression to changes in chromatin accessibility. This study reveals rapid and dramatic epigenomic plasticity in response to a brief, highly consequential social interaction.
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http://dx.doi.org/10.1371/journal.pgen.1006840DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5509087PMC
July 2017

Transcriptional regulatory dynamics drive coordinated metabolic and neural response to social challenge in mice.

Genome Res 2017 06 29;27(6):959-972. Epub 2017 Mar 29.

Carl R. Woese Institute for Genomic Biology, University of Illinois at Urbana-Champaign, Urbana, Illinois 61801, USA.

Agonistic encounters are powerful effectors of future behavior, and the ability to learn from this type of social challenge is an essential adaptive trait. We recently identified a conserved transcriptional program defining the response to social challenge across animal species, highly enriched in transcription factor (TF), energy metabolism, and developmental signaling genes. To understand the trajectory of this program and to uncover the most important regulatory influences controlling this response, we integrated gene expression data with the chromatin landscape in the hypothalamus, frontal cortex, and amygdala of socially challenged mice over time. The expression data revealed a complex spatiotemporal patterning of events starting with neural signaling molecules in the frontal cortex and ending in the modulation of developmental factors in the amygdala and hypothalamus, underpinned by a systems-wide shift in expression of energy metabolism-related genes. The transcriptional signals were correlated with significant shifts in chromatin accessibility and a network of challenge-associated TFs. Among these, the conserved metabolic and developmental regulator ESRRA was highlighted for an especially early and important regulatory role. Cell-type deconvolution analysis attributed the differential metabolic and developmental signals in this social context primarily to oligodendrocytes and neurons, respectively, and we show that ESRRA is expressed in both cell types. Localizing ESRRA binding sites in cortical chromatin, we show that this nuclear receptor binds both differentially expressed energy-related and neurodevelopmental TF genes. These data link metabolic and neurodevelopmental signaling to social challenge, and identify key regulatory drivers of this process with unprecedented tissue and temporal resolution.
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http://dx.doi.org/10.1101/gr.214221.116DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5453329PMC
June 2017

A Hox-Embedded Long Noncoding RNA: Is It All Hot Air?

PLoS Genet 2016 Dec 15;12(12):e1006485. Epub 2016 Dec 15.

HudsonAlpha Institute for Biotechnology, Huntsville, Alabama, United States of America.

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http://dx.doi.org/10.1371/journal.pgen.1006485DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5157941PMC
December 2016

ZSCAN5B and primate-specific paralogs bind RNA polymerase III genes and extra-TFIIIC (ETC) sites to modulate mitotic progression.

Oncotarget 2016 Nov;7(45):72571-72592

Institute for Genomic Biology, University of Illinois at Urbana-Champaign, Urbana, IL, USA.

Mammalian genomes contain hundreds of genes transcribed by RNA Polymerase III (Pol III), encoding noncoding RNAs and especially the tRNAs specialized to carry specific amino acids to the ribosome for protein synthesis. In addition to this well-known function, tRNAs and their genes (tDNAs) serve a variety of other critical cellular functions. For example, tRNAs and other Pol III transcripts can be cleaved to yield small RNAs with potent regulatory activities. Furthermore, from yeast to mammals, active tDNAs and related "extra-TFIIIC" (ETC) loci provide the DNA scaffolds for the most ancient known mechanism of three-dimensional chromatin architecture. Here we identify the ZSCAN5 TF family - including mammalian ZSCAN5B and its primate-specific paralogs - as proteins that occupy mammalian Pol III promoters and ETC sites. We show that ZSCAN5B binds with high specificity to a conserved subset of Pol III genes in human and mouse. Furthermore, primate-specific ZSCAN5A and ZSCAN5D also bind Pol III genes, although ZSCAN5D preferentially localizes to MIR SINE- and LINE2-associated ETC sites. ZSCAN5 genes are expressed in proliferating cell populations and are cell-cycle regulated, and siRNA knockdown experiments suggested a cooperative role in regulation of mitotic progression. Consistent with this prediction, ZSCAN5A knockdown led to increasing numbers of cells in mitosis and the appearance of cells. Together, these data implicate the role of ZSCAN5 genes in regulation of Pol III genes and nearby Pol II loci, ultimately influencing cell cycle progression and differentiation in a variety of tissues.
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http://dx.doi.org/10.18632/oncotarget.12508DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5340127PMC
November 2016

Tbx18 Regulates the Differentiation of Periductal Smooth Muscle Stroma and the Maintenance of Epithelial Integrity in the Prostate.

PLoS One 2016 27;11(4):e0154413. Epub 2016 Apr 27.

Department of Cell and Developmental Biology, University of Illinois at Urbana-Champaign, Urbana, Illinois, United States of America, 61801.

The T-box transcription factor TBX18 is essential to mesenchymal cell differentiation in several tissues and Tbx18 loss-of-function results in dramatic organ malformations and perinatal lethality. Here we demonstrate for the first time that Tbx18 is required for the normal development of periductal smooth muscle stromal cells in prostate, particularly in the anterior lobe, with a clear impact on prostate health in adult mice. Prostate abnormalities are only subtly apparent in Tbx18 mutants at birth; to examine postnatal prostate development we utilized a relatively long-lived hypomorphic mutant and a novel conditional Tbx18 allele. Similar to the ureter, cells that fail to express Tbx18 do not condense normally into smooth muscle cells of the periductal prostatic stroma. However, in contrast to ureter, the periductal stromal cells in mutant prostate assume a hypertrophic, myofibroblastic state and the adjacent epithelium becomes grossly disorganized. To identify molecular events preceding the onset of this pathology, we compared gene expression in the urogenital sinus (UGS), from which the prostate develops, in Tbx18-null and wild type littermates at two embryonic stages. Genes that regulate cell proliferation, smooth muscle differentiation, prostate epithelium development, and inflammatory response were significantly dysregulated in the mutant urogenital sinus around the time that Tbx18 is first expressed in the wild type UGS, suggesting a direct role in regulating those genes. Together, these results argue that Tbx18 is essential to the differentiation and maintenance of the prostate periurethral mesenchyme and that it indirectly regulates epithelial differentiation through control of stromal-epithelial signaling.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0154413PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4847854PMC
March 2017

Roles of progesterone receptor A and B isoforms during human endometrial decidualization.

Mol Endocrinol 2015 Jun 15;29(6):882-95. Epub 2015 Apr 15.

Departments of Molecular and Integrative Physiology (H.S.K., A.M.H., M.K.B.), Cell and Developmental Biology (L.J.S.), and Comparative Biosciences (I.C.B.), University of Illinois at Urbana-Champaign, Urbana, Illinois 61801; and Department of Obstetrics and Gynecology (R.N.T.), Wake Forest University School of Medicine, Winston-Salem, North Carolina 27157.

Progesterone, acting through the progesterone receptors (PGRs), is one of the most critical regulators of endometrial differentiation, known as decidualization, which is a key step toward the establishment of pregnancy. Yet a long-standing unresolved issue in uterine biology is the precise roles played by the major PGR isoforms, PGR-A and PGR-B, during decidualization in the human. Our approach, expressing PGR-A and PGR-B individually after silencing endogenous PGRs in human endometrial stromal cells (HESCs), enabled the analysis of the roles of these isoforms separately as well as jointly. Chromatin immunoprecipitation-sequencing in combination with gene expression profiling revealed that PGR-B controls a substantially larger cistrome and transcriptome than PGR-A during HESC differentiation. Interestingly, PGR-B directly regulates the expression of PGR-A. De novo motif analysis indicated that, although the 2 isoforms bind to the same DNA sequence motif, there are both common and unique neighboring motifs where other transcription factors, such as FOSL1/2, JUN, C/EBPβ, and STAT3, bind and dictate the transcriptional activities of these isoforms. We found that PGR-A and PGR-B regulate overlapping as well as distinct sets of genes, many of which are known to be critical for decidualization and establishment of pregnancy. When PGR-A and PGR-B were coexpressed during HESC differentiation, PGR-B played a predominant role, although both isoforms influenced each other's transcriptional activity. This study revealed the gene networks that operate downstream of each PGR isoform to mediate critical functions, such as regulation of the cell cycle, angiogenesis, lysosomal activation, insulin receptor signaling, and apoptosis, during decidualization in the human.
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http://dx.doi.org/10.1210/me.2014-1363DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4447642PMC
June 2015

Neuromolecular responses to social challenge: common mechanisms across mouse, stickleback fish, and honey bee.

Proc Natl Acad Sci U S A 2014 Dec 1;111(50):17929-34. Epub 2014 Dec 1.

Institute for Genomic Biology, Neuroscience Program, Cell and Developmental Biology,

Certain complex phenotypes appear repeatedly across diverse species due to processes of evolutionary conservation and convergence. In some contexts like developmental body patterning, there is increased appreciation that common molecular mechanisms underlie common phenotypes; these molecular mechanisms include highly conserved genes and networks that may be modified by lineage-specific mutations. However, the existence of deeply conserved mechanisms for social behaviors has not yet been demonstrated. We used a comparative genomics approach to determine whether shared neuromolecular mechanisms could underlie behavioral response to territory intrusion across species spanning a broad phylogenetic range: house mouse (Mus musculus), stickleback fish (Gasterosteus aculeatus), and honey bee (Apis mellifera). Territory intrusion modulated similar brain functional processes in each species, including those associated with hormone-mediated signal transduction and neurodevelopment. Changes in chromosome organization and energy metabolism appear to be core, conserved processes involved in the response to territory intrusion. We also found that several homologous transcription factors that are typically associated with neural development were modulated across all three species, suggesting that shared neuronal effects may involve transcriptional cascades of evolutionarily conserved genes. Furthermore, immunohistochemical analyses of a subset of these transcription factors in mouse again implicated modulation of energy metabolism in the behavioral response. These results provide support for conserved genetic "toolkits" that are used in independent evolutions of the response to social challenge in diverse taxa.
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http://dx.doi.org/10.1073/pnas.1420369111DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4273386PMC
December 2014

A distant downstream enhancer directs essential expression of Tbx18 in urogenital tissues.

Dev Biol 2014 Aug 20;392(2):483-93. Epub 2014 May 20.

Department of Cell & Developmental Biology, University of Illinois, Urbana, IL, USA; Institute for Genomic Biology, University of Illinois, Urbana, IL, USA. Electronic address:

The vertebrate T-box transcription factor gene Tbx18 performs a vital role in development of multiple organ systems. Tbx18 insufficiency manifests as recessive phenotypes in the upper urinary system, cardiac venous pole, inner ear, and axial skeleton; homozygous null mutant animals die perinatally. Here, we report a new regulatory mutation of Tbx18, a reciprocal translocation breaking 78kbp downstream of the gene. 12Gso homozygotes present urinary and vertebral defects very similar to those associated with Tbx18-null mutations, but 12Gso is clearly not a global null allele since homozygotes survive into adulthood. We show that 12Gso down-regulates Tbx18 expression in a manner that is both spatially- and temporally-specific; combined with other data, the mutation points particularly to the presence of an essential urogenital enhancer located near the translocation breakpoint site. In support of this hypothesis, we identify a distal enhancer element, ECR1, which is active in developing urogenital and other tissues; we propose that disruption of this element leads to premature loss of Tbx18 function in 12Gso mutant mice. These data reveal a long-range regulatory architecture extending far downstream of Tbx18, identify a novel and likely essential urogenital enhancer, and introduce a new tool for dissecting postnatal phenotypes associated with dysregulation of Tbx18.
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http://dx.doi.org/10.1016/j.ydbio.2014.05.010DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4104242PMC
August 2014

Deep vertebrate roots for mammalian zinc finger transcription factor subfamilies.

Genome Biol Evol 2014 Mar;6(3):510-25

Center for Biophysics and Computational Biology, University of Illinois, Urbana.

While many vertebrate transcription factor (TF) families are conserved, the C2H2 zinc finger (ZNF) family stands out as a notable exception. In particular, novel ZNF gene types have arisen, duplicated, and diverged independently throughout evolution to yield many lineage-specific TF genes. This evolutionary dynamic not only raises many intriguing questions but also severely complicates identification of those ZNF genes that remain functionally conserved. To address this problem, we searched for vertebrate "DNA binding orthologs" by mining ZNF loci from eight sequenced genomes and then aligning the patterns of DNA-binding amino acids, or "fingerprints," extracted from the encoded ZNF motifs. Using this approach, we found hundreds of lineage-specific genes in each species and also hundreds of orthologous groups. Most groups of orthologs displayed some degree of fingerprint divergence between species, but 174 groups showed fingerprint patterns that have been very rigidly conserved. Focusing on the dynamic KRAB-ZNF subfamily--including nearly 400 human genes thought to possess potent KRAB-mediated epigenetic silencing activities--we found only three genes conserved between mammals and nonmammalian groups. These three genes, members of an ancient familial cluster, encode an unusual KRAB domain that functions as a transcriptional activator. Evolutionary analysis confirms the ancient provenance of this activating KRAB and reveals the independent expansion of KRAB-ZNFs in every vertebrate lineage. Most human ZNF genes, from the most deeply conserved to the primate-specific genes, are highly expressed in immune and reproductive tissues, indicating that they have been enlisted to regulate evolutionarily divergent biological traits.
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http://dx.doi.org/10.1093/gbe/evu030DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3971581PMC
March 2014

A reciprocal translocation dissects roles of Pax6 alternative promoters and upstream regulatory elements in the development of pancreas, brain, and eye.

Genesis 2013 Sep 23;51(9):630-46. Epub 2013 Jul 23.

Genome Biology Division, Lawrence Livermore National Laboratory, Livermore, California.

Pax6 encodes a transcription factor with key roles in the development of the pancreas, central nervous system, and eye. Gene expression is orchestrated by several alternative promoters and enhancer elements that are distributed over several hundred kilobases. Here, we describe a reciprocal translocation, called 1Gso, which disrupts the integrity of transcripts arising from the 5'-most promoter, P0, and separates downstream promoters from enhancers active in pancreas and eye. Despite this fact, 1Gso animals exhibit none of the dominant Pax6 phenotypes, and the translocation complements recessive brain and craniofacial phenotypes. However, 1Gso fails to complement Pax6 recessive effects in lacrimal gland, conjunctiva, lens, and pancreas. The 1Gso animals also express a corneal phenotype that is related to but distinct from that expressed by Pax6 null mutants, and an abnormal density and organization of retinal ganglion cell axons; these phenotypes may be related to a modest upregulation of Pax6 expression from downstream promoters that we observed during development. Our investigation maps the activities of Pax6 alternative promoters including a novel one in developing tissues, confirms the phenotypic consequences of upstream enhancer disruption, and limits the likely effects of the P0 transcript null mutation to recessive abnormalities in the pancreas and specific structures of the eye.
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http://dx.doi.org/10.1002/dvg.22409DOI Listing
September 2013

DNA. Editorial.

Authors:
Lisa Stubbs

Brief Funct Genomics 2012 May;11(3):187

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http://dx.doi.org/10.1093/bfgp/els021DOI Listing
May 2012

Gain, loss and divergence in primate zinc-finger genes: a rich resource for evolution of gene regulatory differences between species.

PLoS One 2011 29;6(6):e21553. Epub 2011 Jun 29.

Institute for Genomic Biology, University of Illinois, Urbana, Illinois, United States of America.

The molecular changes underlying major phenotypic differences between humans and other primates are not well understood, but alterations in gene regulation are likely to play a major role. Here we performed a thorough evolutionary analysis of the largest family of primate transcription factors, the Krüppel-type zinc finger (KZNF) gene family. We identified and curated gene and pseudogene models for KZNFs in three primate species, chimpanzee, orangutan and rhesus macaque, to allow for a comparison with the curated set of human KZNFs. We show that the recent evolutionary history of primate KZNFs has been complex, including many lineage-specific duplications and deletions. We found 213 species-specific KZNFs, among them 7 human-specific and 23 chimpanzee-specific genes. Two human-specific genes were validated experimentally. Ten genes have been lost in humans and 13 in chimpanzees, either through deletion or pseudogenization. We also identified 30 KZNF orthologs with human-specific and 42 with chimpanzee-specific sequence changes that are predicted to affect DNA binding properties of the proteins. Eleven of these genes show signatures of accelerated evolution, suggesting positive selection between humans and chimpanzees. During primate evolution the most extensive re-shaping of the KZNF repertoire, including most gene additions, pseudogenizations, and structural changes occurred within the subfamily homininae. Using zinc finger (ZNF) binding predictions, we suggest potential impact these changes have had on human gene regulatory networks. The large species differences in this family of TFs stands in stark contrast to the overall high conservation of primate genomes and potentially represents a potent driver of primate evolution.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0021553PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3126818PMC
December 2011

Function and Evolution of C2H2 Zinc Finger Arrays.

Subcell Biochem 2011 ;52:75-94

Department of Cell and Developmental Biology, Institute for Genomic Biology, University of Illinois, Urbana, IL, 61801, USA,

Krüppel-type or C2H2 zinc fingers represent a dominant DNA-binding motif in eukaryotic transcription factor (TF) proteins. In Krüppel-type (KZNF) TFs, KZNF motifs are arranged in arrays of three to as many as 40 tandem units, which cooperate to define the unique DNA recognition properties of the protein. Each finger contains four amino acids located at specific positions, which are brought into direct contact with adjacent nucleotides in the DNA sequence as the KZNF array winds around the major groove of the alpha helix. This arrangement creates an intimate and potentially predictable relationship between the amino acid sequence of KZNF arrays and the nucleotide sequence of target binding sites. The large number of possible combinations and arrangements of modular KZNF motifs, and the increasing lengths of KZNF arrays in vertebrate species, has created huge repertoires of functionally unique TF proteins. The properties of this versatile DNA-binding motif have been exploited independently many times over the course of evolution, through attachment to effector motifs that confer activating, repressing or other activities to the proteins. Once created, some of these novel inventions have expanded in specific evolutionary clades, creating large families of TFs that are lineage- or species-unique. This chapter reviews the properties and their remarkable evolutionary history of eukaryotic KZNF TF proteins, with special focus on large families that dominate the TF landscapes in different metazoan species.
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http://dx.doi.org/10.1007/978-90-481-9069-0_4DOI Listing
April 2016

Rapid sequence and expression divergence suggest selection for novel function in primate-specific KRAB-ZNF genes.

Mol Biol Evol 2010 Nov 23;27(11):2606-17. Epub 2010 Jun 23.

Institute for Genomic Biology, University of Illinois at Urbana-Champaign, USA.

Recent segmental duplications (SDs), arising from duplication events that occurred within the past 35-40 My, have provided a major resource for the evolution of proteins with primate-specific functions. KRAB zinc finger (KRAB-ZNF) transcription factor genes are overrepresented among genes contained within these recent human SDs. Here, we examine the structural and functional diversity of the 70 human KRAB-ZNF genes involved in the most recent primate SD events including genes that arose in the hominid lineage. Despite their recent advent, many parent-daughter KRAB-ZNF gene pairs display significant differences in zinc finger structure and sequence, expression, and splicing patterns, each of which could significantly alter the regulatory functions of the paralogous genes. Paralogs that emerged on the lineage to humans and chimpanzees have undergone more evolutionary changes per unit of time than genes already present in the common ancestor of rhesus macaques and great apes. Taken together, these data indicate that a substantial fraction of the recently evolved primate-specific KRAB-ZNF gene duplicates have acquired novel functions that may possibly define novel regulatory pathways and suggest an active ongoing selection for regulatory diversity in primates.
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http://dx.doi.org/10.1093/molbev/msq157DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2981486PMC
November 2010

Lineage-specific transcription factors and the evolution of gene regulatory networks.

Brief Funct Genomics 2010 Jan 16;9(1):65-78. Epub 2010 Jan 16.

Department of Cell and Developmental Biology, Institute for Genomic Biology, University of Illinois, 1206 W. Gregory Drive, Urbana, IL 61802, USA.

Nature is replete with examples of diverse cell types, tissues and body plans, forming very different creatures from genomes with similar gene complements. However, while the genes and the structures of proteins they encode can be highly conserved, the production of those proteins in specific cell types and at specific developmental time points might differ considerably between species. A full understanding of the factors that orchestrate gene expression will be essential to fully understand evolutionary variety. Transcription factor (TF) proteins, which form gene regulatory networks (GRNs) to act in cooperative or competitive partnerships to regulate gene expression, are key components of these unique regulatory programs. Although many TFs are conserved in structure and function, certain classes of TFs display extensive levels of species diversity. In this review, we highlight families of TFs that have expanded through gene duplication events to create species-unique repertoires in different evolutionary lineages. We discuss how the hierarchical structures of GRNs allow for flexible small to large-scale phenotypic changes. We survey evidence that explains how newly evolved TFs may be integrated into an existing GRN and how molecular changes in TFs might impact the GRNs. Finally, we review examples of traits that evolved due to lineage-specific TFs and species differences in GRNs.
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http://dx.doi.org/10.1093/bfgp/elp056DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3096533PMC
January 2010

Differences in human and chimpanzee gene expression patterns define an evolving network of transcription factors in brain.

Proc Natl Acad Sci U S A 2009 Dec 10;106(52):22358-63. Epub 2009 Dec 10.

Department of Cell and Developmental Biology, Institute for Genomic Biology, University of Illinois at Urbana-Champaign, Urbana, IL 61801, USA.

Humans differ from other primates by marked differences in cognitive abilities and a significantly larger brain. These differences correlate with metabolic changes, as evidenced by the relative up-regulation of energy-related genes and metabolites in human brain. While the mechanisms underlying these evolutionary changes have not been elucidated, altered activities of key transcription factors (TFs) could play a pivotal role. To assess this possibility, we analyzed microarray data from five tissues from humans and chimpanzees. We identified 90 TF genes with significantly different expression levels in human and chimpanzee brain among which the rapidly evolving KRAB-zinc finger genes are markedly over-represented. The differentially expressed TFs cluster within a robust regulatory network consisting of two distinct but interlinked modules, one strongly associated with energy metabolism functions, and the other with transcription, vesicular transport, and ubiquitination. Our results suggest that concerted changes in a relatively small number of interacting TFs may coordinate major gene expression differences in human and chimpanzee brain.
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http://dx.doi.org/10.1073/pnas.0911376106DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2799715PMC
December 2009

Germline translocations in mice: unique tools for analyzing gene function and long-distance regulatory mechanisms.

J Natl Cancer Inst Monogr 2008 (39):91-5

Genome Biology, Lawrence Livermore National Laboratory, 7000 East Ave, L-452, Livermore CA 94550, USA.

Translocations have provided invaluable tools for identifying both cancer-linked genes and loci associated with heritable human diseases, but heritable human translocations are rare and few mouse models exist. Here we report progress on analysis of a collection of heritable translocations generated by treatment of mice with specific chemicals or radiation during late spermatogenic stages. The translocation mutants exhibit a range of visible phenotypes reflecting the disruption of coding sequences or the separation of genes from essential regulatory elements. The breakpoints of both radiation-induced and chemically induced mutations in these mice are remarkably clean, with very short deletions, duplications, or inversions in some cases, and ligation mediated by microhomology, suggesting nonhomologous end joining as the major path of repair. These mutations provide new tools for the discovery of novel genes and regulatory elements linked to human developmental disorders and new clues to the molecular basis of human genetic disease.
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http://dx.doi.org/10.1093/jncimonographs/lgn008DOI Listing
September 2008

Comparative analysis of chicken chromosome 28 provides new clues to the evolutionary fragility of gene-rich vertebrate regions.

Genome Res 2007 Nov 5;17(11):1603-13. Epub 2007 Oct 5.

Genome Biology Group, Lawrence Livermore National Laboratory, Livermore, California 94550, USA.

The chicken genome draft sequence has provided a valuable resource for studies of an important agricultural and experimental model species and an important data set for comparative analysis. However, some of the most gene-rich segments are missing from chicken genome draft assemblies, limiting the analysis of a substantial number of genes and preventing a closer look at regions that are especially prone to syntenic rearrangements. To facilitate the functional and evolutionary analysis of one especially gene-rich, rearrangement-prone genomic region, we analyzed sequence from BAC clones spanning chicken microchromosome GGA28; as a complement we also analyzed a gene-sparse, stable region from GGA11. In these two regions we documented the conservation and lineage-specific gain and loss of protein-coding genes and precisely mapped the locations of 31 major human-chicken syntenic breakpoints. Altogether, we identified 72 lineage-specific genes, many of which are found at or near syntenic breaks, implicating evolutionary breakpoint regions as major sites of genetic innovation and change. Twenty-two of the 31 breakpoint regions have been reused repeatedly as rearrangement breakpoints in vertebrate evolution. Compared with stable GC-matched regions, GGA28 is highly enriched in CpG islands, as are break-prone intervals identified elsewhere in the chicken genome; evolutionary breakpoints are further enriched in GC content and CpG islands, highlighting a potential role for these features in genome instability. These data support the hypothesis that chromosome rearrangements have not occurred randomly over the course of vertebrate evolution but are focused preferentially within "fragile" regions with unusual DNA sequence characteristics.
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http://dx.doi.org/10.1101/gr.6775107DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2045143PMC
November 2007

Genomic organization and imprinting of the Peg3 domain in bovine.

Genomics 2007 Jul 16;90(1):85-92. Epub 2007 May 16.

Department of Biological Sciences, Louisiana State University, Baton Rouge, LA 70803, USA.

Using multiple mammalian genomic sequences, we have analyzed the evolution and imprinting of several genes located in the Peg3 domain, including Mim1 (approved name, Mimt1), Usp29, Zim3, and Zfp264. A series of comparative analyses shows that the overall genomic structure of this 500-kb imprinted domain has been well maintained throughout mammalian evolution but that several lineage-specific changes have also occurred in each species. In the bovine domain, Usp29 has lost its protein-coding capability, Zim3 has been duplicated, and the expression of Zfp264 has become biallelic in brain and testis, which differs from paternal expression of mouse Zfp264 in brain. In contrast, the two transcript genes of cow, Mim1 and Usp29, both lacking protein-coding capability, are still expressed mainly from the paternal allele, indicating the imprinting of these two genes in cow. The imprinting of Mim1 and Usp29 along with Peg3 is the most evolutionarily selected feature in this imprinted domain, suggesting significant function of these three genes, either as protein-coding or as untranslated transcript genes.
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http://dx.doi.org/10.1016/j.ygeno.2007.03.012DOI Listing
July 2007

YY1 as a controlling factor for the Peg3 and Gnas imprinted domains.

Genomics 2007 Feb 25;89(2):262-9. Epub 2006 Oct 25.

Department of Biological Sciences, Center for BioModular Multi-Scale Systems, Louisiana State University, Baton Rouge, LA 70803, USA.

Imprinting control regions (ICRs) often harbor tandem arrays of transcription factor binding sites, as demonstrated by the identification of multiple YY1 binding sites within the ICRs of Peg3, Nespas, and Xist/Tsix domains. In the current study, we have sought to characterize possible roles for YY1 in transcriptional control and epigenetic modification of these imprinted domains. RNA interference-based knockdown experiments in Neuro2A cells resulted in overall transcriptional up-regulation of most of the imprinted genes within the Peg3 domain and also, concomitantly, caused significant loss in the DNA methylation of the Peg3 differentially methylated region. A similar overall and coordinated expression change was also observed for the imprinted genes of the Gnas domain: up-regulation of Nespas and down-regulation of Nesp and Gnasxl. YY1 knockdown also resulted in changes in the expression levels of Xist and Snrpn. These results support the idea that YY1 plays a major role, as a trans factor, in the control of these imprinted domains.
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http://dx.doi.org/10.1016/j.ygeno.2006.09.009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1828871PMC
February 2007

Identification of clustered YY1 binding sites in imprinting control regions.

Genome Res 2006 Jul 7;16(7):901-11. Epub 2006 Jun 7.

Department of Biological Sciences, Center for BioModular Multi-Scale Systems, Louisiana State University, Baton Rouge, Louisiana 70803, USA.

Mammalian genomic imprinting is regulated by imprinting control regions (ICRs) that are usually associated with tandem arrays of transcription factor binding sites. In this study, the sequence features derived from a tandem array of YY1 binding sites of Peg3-DMR (differentially methylated region) led us to identify three additional clustered YY1 binding sites, which are also localized within the DMRs of Xist, Tsix, and Nespas. These regions have been shown to play a critical role as ICRs for the regulation of surrounding genes. These ICRs have maintained a tandem array of YY1 binding sites during mammalian evolution. The in vivo binding of YY1 to these regions is allele specific and only to the unmethylated active alleles. Promoter/enhancer assays suggest that a tandem array of YY1 binding sites function as a potential orientation-dependent enhancer. Insulator assays revealed that the enhancer-blocking activity is detected only in the YY1 binding sites of Peg3-DMR but not in the YY1 binding sites of other DMRs. Overall, our identification of three additional clustered YY1 binding sites in imprinted domains suggests a significant role for YY1 in mammalian genomic imprinting.
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http://dx.doi.org/10.1101/gr.5091406DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1484457PMC
July 2006

Evolutionary expansion and divergence in the ZNF91 subfamily of primate-specific zinc finger genes.

Genome Res 2006 May 10;16(5):584-94. Epub 2006 Apr 10.

Genome Biology Division, Lawrence Livermore National Laboratory, Livermore, California 94550, USA.

Most genes are conserved in mammals, but certain gene families have acquired large numbers of lineage-specific loci through repeated rounds of gene duplication, divergence, and loss that have continued in each mammalian group. One such family encodes KRAB-zinc finger (KRAB-ZNF) proteins, which function as transcriptional repressors. One particular subfamily of KRAB-ZNF genes, including ZNF91, has expanded specifically in primates to comprise more than 110 loci in the human genome. Genes of the ZNF91 subfamily reside in large gene clusters near centromeric regions of human chromosomes 19 and 7 with smaller clusters or isolated copies in other locations. Phylogenetic analysis indicates that many of these genes arose before the split between the New and Old World monkeys, but the ZNF91 subfamily has continued to expand and diversify throughout the evolution of apes and humans. Paralogous loci are distinguished by divergence within their zinc finger arrays, indicating selection for proteins with different regulatory targets. In addition, many loci produce multiple alternatively spliced transcripts encoding proteins that may serve separate and perhaps even opposing regulatory roles because of the modular motif structure of KRAB-ZNF genes. The tissue-specific expression patterns and rapid structural divergence of ZNF91 subfamily genes suggest a role in determining gene expression differences between species and the evolution of novel primate traits.
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http://dx.doi.org/10.1101/gr.4843906DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1457049PMC
May 2006