| 1. |
- Ghazal, Awaisa
(författare)
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Bioinformatics studies on the mechanisms of gene regulation in vertebrates
- 2014
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Gene regulation implicates an important role in organismal complexity through contributing to phenotypic variation. In my thesis, I studied three diverse components of gene regulatory networks including transcription factors, DNA methylation and microRNAs to elucidate their role in vertebrates. The first three studies concern a recently identified transcription factor called ZBED6 and the fourth study is based on analysis of chicken miRNAs. First study focused on phylogenetic reconstruction of the ZBED gene family, which is comprised of ZBED1, ZBED2, ZBED3, ZBED4, ZBED5 and ZBED6. This study demonstrated that ZBEDs arose from at least two independent transposon domestication events in jawed vertebrate ancestors and also identified a new member of this gene family named C7ORF29. Second study focused on the role of ZBED6 in colon adenocarcinoma. We scanned DNA methylation and RNA sequencing data generated from colon adenocarcinoma tumor and normal tissues. This analysis unraveled a list of potential ZBED6 binding sites that were hypermethylated and showed a negative correlation with gene expression data. This candidate list contained several genes with a known role in cancer development and showed that in addition to the ZBED6 binding sites another transcription factor PAX5 binding sites were located in its close vicinity. In the third study, functional analyses of ZBED6 were performed. This study revealed that ZBED6 regulates muscle proteins by directly regulating IGF2 and Twist2 transcription. Analysis of histone modifications showed that ZBED6 preferentially binds with active promoters to modulate transcriptional activity rather than recruiting repressive histone marks. In the fourth study, potential role of miRNAs in differential growth of two extremely divergent chicken lines was investigated. Our analysis revealed the expression of both known and novel miRNAs in three tissues hypothalamus, liver and pectoralis major muscle of chickens. This study provides a detailed insight into the miRNA expression pattern and suggests an association of miRNAs with growth in chickens. These studies on diverse components will add valuable knowledge to existing information in gene regulatory networks and facilitate in future investigations to reveal regulatory mechanisms underlying diverse biological processes.
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| 2. |
- Hayward, Alexander, et al.
(författare)
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ZBED Evolution : Repeated Utilization of DNA Transposons as Regulators of Diverse Host Functions
- 2013
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Ingår i: PLOS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 8:3, s. e59940-
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Tidskriftsartikel (refereegranskat)abstract
- ZBED genes originate from domesticated hAT DNA transposons and encode regulatory proteins of diverse function in vertebrates. Here we reveal the evolutionary relationship between ZBED genes and demonstrate that they are derived from at least two independent domestication events in jawed vertebrate ancestors. We show that ZBEDs form two monophyletic clades, one of which has expanded through several independent duplications in host lineages. Subsequent diversification of ZBED genes has facilitated regulation of multiple diverse fundamental functions. In contrast to known examples of transposable element exaptation, our results demonstrate a novel unprecedented capacity for the repeated utilization of a family of transposable element-derived protein domains sequestered as regulators during the evolution of diverse host gene functions in vertebrates. Specifically, ZBEDs have contributed to vertebrate regulatory innovation through the donation of modular DNA and protein interacting domains. We identify that C7ORF29, ZBED2, 3, 4, and ZBEDX form a monophyletic group together with ZBED6, that is distinct from ZBED1 genes. Furthermore, we show that ZBED5 is related to Buster DNA transposons and is phylogenetically separate from other ZBEDs. Our results offer new insights into the evolution of regulatory pathways, and suggest that DNA transposons have contributed to regulatory complexity during genome evolution in vertebrates.
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| 3. |
- Jiang, Lin, et al.
(författare)
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The role of ZBED6 in transcriptional regulation studied by transcriptome analysis after RNAi in mouse myoblasts
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Forskningsöversikt (övrigt vetenskapligt/konstnärligt)abstract
- ZBED6 is a recently discovered transcription factor that has evolved from a domesticated DNA transposon and is unique to placental mammals. Here we further characterize the functional significance of ZBED6 based on transcriptome analysis of mouse myoblasts after Zbed6-silencing. ZBED6 appears as an important transcriptional regulator since differential expression of more than 700 genes was observed after Zbed6-silencing. The most significantly enriched GO term was muscle protein and contractile fiber, which is consistent with increased myotube formation. Twenty small nucleolar RNAs showed differential expression and all increased in expression after Zbed6-silencing. This is particularly interesting because ZBED6 localization is strongly enriched in the nucleolus. There was an overrepresentation of genes with ZBED6 binding sites among the differentially expressed genes after silencing, suggesting that ZBED6 acts as a transcriptional regulator at many loci. Many genes showed significant down-regulation after Zbed6-silencing, which begs the question of whether ZBED6 acts as an activator at some of these loci or if the decreased mRNA levels of these genes all represent secondary effects. The co-localization of histone marks and ZBED6 binding sites and the effect of ZBED6-silencing on distribution of histone marks was evaluated by ChIP-seq. There was a strong association between ZBED6 binding sites and the H3K4me3, H3K4me2 and H3K27ac modifications, which are usually found at active promoters, but no association with the repressive marks H3K27me3. We propose that ZBED6 preferentially binds to active promoters and modulates transcriptional activity by a novel mechanism rather than by recruiting repressive histone modifications.
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| 4. |
- Jiang, Lin, et al.
(författare)
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ZBED6 Modulates the Transcription of Myogenic Genes in Mouse Myoblast Cells
- 2014
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Ingår i: PLOS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 9:4, s. e94187-
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Tidskriftsartikel (refereegranskat)abstract
- ZBED6 is a recently discovered transcription factor, unique to placental mammals, that has evolved from a domesticated DNA transposon. It acts as a repressor at the IGF2 locus. Here we show that ZBED6 acts as a transcriptional modulator in mouse myoblast cells, where more than 700 genes were differentially expressed after Zbed6-silencing. The most significantly enriched GO term was muscle protein and contractile fiber, which was consistent with increased myotube formation. Twenty small nucleolar RNAs all showed increased expression after Zbed6-silencing. The co-localization of histone marks and ZBED6 binding sites and the effect of Zbed6-silencing on distribution of histone marks was evaluated by ChIP-seq analysis. There was a strong association between ZBED6 binding sites and the H3K4me3, H3K4me2 and H3K27ac modifications, which are usually found at active promoters, but no association with the repressive mark H3K27me3. Zbed6-silencing led to increased enrichment of active marks at myogenic genes, in agreement with the RNA-seq findings. We propose that ZBED6 preferentially binds to active promoters and modulates transcriptional activity without recruiting repressive histone modifications.
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