Favorable genomic environments for cis-regulatory evolution: A novel theoretical framework

Maeso, Ignacio; Tena, Juan J.

doi:10.1016/j.semcdb.2015.12.003

Cited by 17 publications

(18 citation statements)

References 112 publications

(140 reference statements)

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“…Furthermore, the Msx -CNE ( Msx -CNE-1), 5’ of the coding sequence, and one ZNF503/703 -CNE ( ZNF503/703 -CNE-1) have been experimentally verified by previous studies (Holland et al 2008; Hufton et al 2009; Royo et al 2011; Clarke et al 2012). Finally, for all of these eight cephalochordate-vertebrate CNEs, we found that the sequence conservation between the two cephalochordates ( A. lucayanum and B. floridae ) clearly extends beyond the core CNE regions, echoing the trend previously observed in vertebrates (McEwen et al 2009; Maeso and Tena 2016) that flanking sequences of ancient CNEs tend to be more conserved between more closely related lineages. …”

Section: Resultssupporting

confidence: 81%

“…Similarly, in vertebrates, some CNEs associated with GLI3 , which transduces Shh signaling, show conserved expression in mouse and zebrafish, while one CNE, which directs expression to the limb bud in the mouse and chick, directs expression to the notochord and blood cell precursors, but not to the limb, in the zebrafish (Anwar et al 2015). In fact, such examples of acquiring new regulatory functions by co-option or modification of preexisting CNEs are prevalent in the evolution of new regulatory elements (Maeso and Tena 2016). …”

Section: Discussionmentioning

confidence: 99%

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Conserved Noncoding Elements in the Most Distant Genera of Cephalochordates: The Goldilocks Principle

et al. 2016

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Cephalochordates, the sister group of vertebrates + tunicates, are evolving particularly slowly. Therefore, genome comparisons between two congeners of Branchiostoma revealed so many conserved noncoding elements (CNEs), that it was not clear how many are functional regulatory elements. To more effectively identify CNEs with potential regulatory functions, we compared noncoding sequences of genomes of the most phylogenetically distant cephalochordate genera, Asymmetron and Branchiostoma, which diverged approximately 120–160 million years ago. We found 113,070 noncoding elements conserved between the two species, amounting to 3.3% of the genome. The genomic distribution, target gene ontology, and enriched motifs of these CNEs all suggest that many of them are probably cis-regulatory elements. More than 90% of previously verified amphioxus regulatory elements were re-captured in this study. A search of the cephalochordate CNEs around 50 developmental genes in several vertebrate genomes revealed eight CNEs conserved between cephalochordates and vertebrates, indicating sequence conservation over >500 million years of divergence. The function of five CNEs was tested in reporter assays in zebrafish, and one was also tested in amphioxus. All five CNEs proved to be tissue-specific enhancers. Taken together, these findings indicate that even though Branchiostoma and Asymmetron are distantly related, as they are evolving slowly, comparisons between them are likely optimal for identifying most of their tissue-specific cis-regulatory elements laying the foundation for functional characterizations and a better understanding of the evolution of developmental regulation in cephalochordates.

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Section: Resultssupporting

confidence: 81%

Section: Discussionmentioning

confidence: 99%

Conserved Noncoding Elements in the Most Distant Genera of Cephalochordates: The Goldilocks Principle

et al. 2016

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“…De-repression/activation of cryptic (or normally dormant) promoters to drive ectopic expression is one mechanism that can lead to oncogenic effects [34–40]. Because TEs, and especially ERV LTRs, are an abundant reservoir of natural promoters in the human genome [6, 41, 42], inappropriate transcriptional activation of typically repressed LTRs may contribute to oncogenesis. Here we review examples of such phenomena, which we term “onco-exaptation”, and propose two explanatory models to understand the role of LTRs in oncogenesis.…”

Section: Introductionmentioning

confidence: 99%

Endogenous retroviral promoter exaptation in human cancer

2016

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Cancer arises from a series of genetic and epigenetic changes, which result in abnormal expression or mutational activation of oncogenes, as well as suppression/inactivation of tumor suppressor genes. Aberrant expression of coding genes or long non-coding RNAs (lncRNAs) with oncogenic properties can be caused by translocations, gene amplifications, point mutations or other less characterized mechanisms. One such mechanism is the inappropriate usage of normally dormant, tissue-restricted or cryptic enhancers or promoters that serve to drive oncogenic gene expression. Dispersed across the human genome, endogenous retroviruses (ERVs) provide an enormous reservoir of autonomous gene regulatory modules, some of which have been co-opted by the host during evolution to play important roles in normal regulation of genes and gene networks. This review focuses on the “dark side” of such ERV regulatory capacity. Specifically, we discuss a growing number of examples of normally dormant or epigenetically repressed ERVs that have been harnessed to drive oncogenes in human cancer, a process we term onco-exaptation, and we propose potential mechanisms that may underlie this phenomenon.

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“…One underappreciated mechanism that can cause gene deregulation in cancer is activation of cryptic (or normally dormant) promoters [1–4]. Transposable elements (TEs), including endogenous retroviruses (ERVs) and long interspersed elements (LINEs), comprise nearly half of the human genome [5–7] and represent an abundant source of natural promoters in the genome [8, 9]. In particular, ERV long terminal repeats (LTRs), the termini of integrated retroviruses, naturally harbor promoters and enhancers.…”

Section: Introductionmentioning

confidence: 99%

A novel isoform of IL-33 revealed by screening for transposable element promoted genes in human colorectal cancer

et al. 2017

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Remnants of ancient transposable elements (TEs) are abundant in mammalian genomes. These sequences contain multiple regulatory motifs and hence are capable of influencing expression of host genes. TEs are known to be released from epigenetic repression and can become transcriptionally active in cancer. Such activation could also lead to lineage-inappropriate activation of oncogenes, as previously described in lymphomas. However, there are few reports of this mechanism occurring in non-blood cancers. Here, we re-analyzed whole transcriptome data from a large cohort of patients with colon cancer, compared to matched normal colon control samples, to detect genes or transcripts ectopically expressed through activation of TE promoters. Among many such transcripts, we identified six where the affected gene has described role in cancer and where the TE-driven gene mRNA is expressed in primary colon cancer, but not normal matched tissue, and confirmed expression in colon cancer-derived cell lines. We further characterized a TE-gene chimeric transcript involving the Interleukin 33 (IL-33) gene (termed LTR-IL-33), that is ectopically expressed in a subset of colon cancer samples through the use of an endogenous retroviral long terminal repeat (LTR) promoter of the MSTD family. The LTR-IL-33 chimeric transcript encodes a novel shorter isoform of the protein, which is missing the initial N-terminus (including many conserved residues) of Native IL-33. In vitro studies showed that LTR-IL-33 expression is required for optimal CRC cell line growth as 3D colonospheres. Taken together, these data demonstrate the significance of TEs as regulators of aberrant gene expression in colon cancer.

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Favorable genomic environments for cis-regulatory evolution: A novel theoretical framework

Cited by 17 publications

References 112 publications

Conserved Noncoding Elements in the Most Distant Genera of Cephalochordates: The Goldilocks Principle

Conserved Noncoding Elements in the Most Distant Genera of Cephalochordates: The Goldilocks Principle

Endogenous retroviral promoter exaptation in human cancer

A novel isoform of IL-33 revealed by screening for transposable element promoted genes in human colorectal cancer

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