Large clusters of co-expressed genes in the Drosophila genome

Boutanaev, Alexander M.; Kalmykova, Alla; Shevelyov, Yuri Y.; Nurminsky, Dmitry I.

doi:10.1038/nature01216

Cited by 291 publications

(264 citation statements)

References 21 publications

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“…Recently, growing evidence suggests that genes are not randomly distributed along chromosomes. In fact, the clustering of nonhomologous genes coexpressed under similar conditions and involved in common biological processes has been described in worms (Blumenthal et al, 2002), flies (Boutanaev et al, 2002;Cohen et al, 2000) and mammals (Soury et al, 2001;Lercher et al, 2002). These findings suggest that to achieve a complex biological pathway, the coordinate expression of several clustered genes present in open chromatin regions may be advantageous.…”

Section: Discussionmentioning

confidence: 83%

Metastatic lymph node 64 (MLN64), a gene overexpressed in breast cancers, is regulated by Sp/KLF transcription factors

et al. 2003

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MLN64, is invariably coamplified and coexpressed with erbB-2 in breast cancers. The human MLN64 and ERBB2 genes are positioned at less than 50 kb from each other, on chromosome 17q12. To understand the molecular basis of MLN64 overexpression in cancer, the genomic region containing the MLN64 and ERBB2 genes was isolated and mapped. The two genes, DARPP32 and Telethonin, flanking MLN64 respectively on its centromeric and telomeric sides, although coamplified, are not overexpressed in breast cancer cells, indicating that gene amplification is not sufficient to allow overexpression. The MLN64 minimal promoter was isolated and found to be a housekeeping gene promoter containing four potential Sp1 binding elements. Using Sp1-deficient Drosophila SL2 cells, MLN64 promoter activity was induced in a dosedependent manner by exogenous Sp1 addition. Furthermore, mutation of each individual Sp1 element resulted in a significant decrease in reporter gene activity, indicating that all the Sp1 binding elements are functional and act together to promote gene expression. Since the ERBB2 promoter is also positively regulated by Sp1, this study indicates that MLN64 and ERBB2 genes share common transcriptional controls together with a physical link on chromosome 17q. We speculate that, in addition to the oncogenic potential of erbB-2 overexpression, the unbalanced action of MLN64 contributes to the poor clinical outcome of breast tumors bearing this amplified region.

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Section: Discussionmentioning

confidence: 83%

Metastatic lymph node 64 (MLN64), a gene overexpressed in breast cancers, is regulated by Sp/KLF transcription factors

et al. 2003

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“…4) and probably form part of the same stable dicistronic pre-mRNA. 3 Clusters of co-expressed genes were identified in both lower and higher eukaryote cells (34). Moreover, in the particular case of lower eukaryotes, gene clusters or operons that share certain aspects of transcriptional regulation were found in pairs (35,36).…”

Section: Discussionmentioning

confidence: 99%

RNA Recognition Motif-type RNA-binding Proteins in Trypanosoma cruzi Form a Family Involved in the Interaction with Specific Transcripts in Vivo

Gaudenzi¹,

D’Orso²,

Frasch

2003

Journal of Biological Chemistry

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Trypanosomes, protozoan parasites from the order Kinetoplastida, have to deal with environmental changes during the interaction with their hosts. Trypanosoma cruzi, the causative agent of Chagas' disease, uses post-transcriptional mechanisms to regulate gene expression. However, few RNA-binding proteins involved in mRNA turnover control have been identified to date. In this work, an RNA recognition motif (RRM)-type RNA-binding protein family named T. cruzi RNAbinding protein (TcRBP) and composed of at least six members was identified. The genomic organization of four members revealed a head to tail arrangement within a region of 15 kilobase pairs. TcRBP members have a common RRM and different auxiliary domains with a high content of glycine, glutamine, and histidine residues within their N-and C-terminal regions. TcRBPs differ in their expression patterns as well as in their homoribopolymer binding interaction in vitro, although they preferentially recognize poly(U) and poly(G) RNAs. An interesting observation was the relaxed RNA-binding interactions with several trypanosome transcripts in vitro. In contrast, co-immunoprecipitation experiments of TcRBP-containing ribonucleoprotein complexes formed in vivo revealed a highly restricted binding interaction with specific RNAs. Several TcRBPcontaining complexes are stage-specific and, in some cases, bear the poly(A)-binding protein TcPABP1. Altogether, these results suggest that TcRBPs might be modulated in vivo, to favor or preclude the interaction with specific transcripts in a developmentally regulated manner.Trypanosoma cruzi, the etiological agent of Chagas' disease, is a unicellular digenetic protozoan parasite with a complex life cycle that alternates between an insect and a vertebrate host, with different replicative and infective stages in both organisms. The parasite has a wide range of mammalian hosts, from humans to wild and domestic animal species, that act as reservoirs (1). T. cruzi infection is established in the mammal by the insect-derived stage metacyclic trypomastigote that differentiates to the intracellular replicative amastigote stage. This parasite form differentiates to the infective trypomastigote in the mammal, which is released from cells and circulates in blood, infecting other cells and being eventually ingested by the insect with its blood meal. Ingested trypomastigotes differentiate to epimastigotes (the replicative insect stage) that migrate along the digestive tract until differentiation into metacyclic trypomastigotes that are eliminated with the feces closing the cycle. Because the parasite suffers continuous environmental changes, it needs to regulate the expression of many proteins to allow its rapid adaptation. In contrast to other eukaryotic organisms, trypanosomatids do not regulate gene expression at the classical level of transcription initiation (2), although an RNA polymerase II transcriptional complex was recently identified (3). Transcription in these organisms is polycistronic, and the main point of regulation of gene e...

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“…Importantly, the grouped genes show highly correlated levels of expression, suggesting that the domain organization is a reflection of an active chromatin structure that stretches through the region. An analysis of expressed sequence tags (ESTs) databases has also demonstrated the clustering of genes within the Drosophila genome; however, this examination focused on the tissue-specific expression profiles from the testis, head-region, and embryo (Boutanaev et al 2002). In each cell type, the coregulated genes were found to be significantly organized into clusters of three or more genes, with a trend toward large groupings.…”

Section: Flymentioning

confidence: 99%

Form follows function: the genomic organization of cellular differentiation

Kosak¹,

Groudine²

2004

Genes Dev.

218

179

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The extent to which the nucleus is functionally organized has broad biological implications. Evidence supports the idea that basic nuclear functions, such as transcription, are structurally integrated within the nucleus. Moreover, recent studies indicate that the linear arrangement of genes within eukaryotic genomes is nonrandom. We suggest that determining the relationship between nuclear organization and the linear arrangement of genes will lead to a greater understanding of how transcriptomes, dedicated to a particular cellular function or fate, are coordinately regulated. Current network theories may provide a useful framework for modeling the inherent complexity the functional organization of the nucleus.Louis Sullivan, whose early efforts helped pioneer the development of the skyscraper, is considered one of the most important architects of the last century. However, it is his dictum-"form ever follows function"-for which he is perhaps best known. Just as this imperative has influenced generations of architects, the idea that structure reflects function provides a useful perspective for a biologist's view of the cell. In many ways, the structure and function of cellular and subcellular organelles are inseparable; that is, disruptions in organelle function can lead to perturbations in its structure. Upon inhibition of rRNA transcription, for example, the nucleolus becomes disordered and ultimately disappears (Leung and Lamond 2003). This integration of structure and cellular function allows for conservation of resources and facilitates regulation at multiple levels.Although a completely sequenced genome may represent a genetic blueprint, molecular biologists currently lack a key with which to fully grasp how this sequence is related to the development and subsequent maintenance of a given organism. Following Sullivan's example, a comprehensive understanding of genomic sequence may require considering its arrangement in the nucleus; the form DNA takes in the nucleus reveals not only its higher-order structure, but it may impart information regarding its function. The current paradigm of gene regulation includes the binding of site-specific transcription factors, the recruitment of cofactors and general transcription factors, and the incorporation of multiple modifications to both the DNA and the histones that organize it (Felsenfeld and Groudine 2003). This description of transcription belies its enormous complexity, fueled by an ever-increasing catalog of proteins dedicated in one way or another to its regulation. Additionally, evidence supporting the role of nuclear localization in transcriptional regulation indicates that it is insufficient to know the components of transcription . Rather, a thorough understanding of the process requires knowing its functional organization within the nucleus. In this sense, transcription should not be viewed simply as a process that turns on a specific gene, but as a process that governs within the genome an entire network of genes (a transcriptome) that gives rise to a p...

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Large clusters of co-expressed genes in the Drosophila genome

Cited by 291 publications

References 21 publications

Metastatic lymph node 64 (MLN64), a gene overexpressed in breast cancers, is regulated by Sp/KLF transcription factors

Metastatic lymph node 64 (MLN64), a gene overexpressed in breast cancers, is regulated by Sp/KLF transcription factors

RNA Recognition Motif-type RNA-binding Proteins in Trypanosoma cruzi Form a Family Involved in the Interaction with Specific Transcripts in Vivo

Form follows function: the genomic organization of cellular differentiation

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