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Transcriptional Co-Regulation of Micrornas and Protein-Coding Genes

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Transcriptional Co-Regulation of Micrornas and Protein-Coding Genes Transcriptional co-regulation of microRNAs and protein-coding genes A thesis submitted to the University of Manchester for the degree of Doctor of Philosophy in the Faculty of Life Sciences 2013 By Aaron Webber Table of Contents Abstract ......................................................................................................................................... 8 Declaration .................................................................................................................................... 9 Copyright statement ................................................................................................................... 10 Acknowledgements ..................................................................................................................... 11 Preface ........................................................................................................................................ 12 Chapter 1: Introduction .............................................................................................................. 13 1.1 The protein-coding gene expression pathway ............................................................ 13 1.2 Regulation of transcription ......................................................................................... 17 1.2.1 Transcription factors ........................................................................................... 19 1.2.2 Transcriptional regulatory regions ...................................................................... 22 1.3 The physical architecture of DNA ............................................................................... 23 1.4 Alternative transcription and alternative splicing ..................................................... 25 1.5 RNA processing and transport to the ribosome ......................................................... 27 1.6 Post-transcriptional gene silencing ............................................................................ 28 1.6.1 MicroRNAs .......................................................................................................... 29 1.6.2 Mechanisms of microRNA-mediated gene repression ....................................... 32 1.7 Protein folding and post-translational modification................................................... 35 1.8 Crosstalk between the regulators of gene expression ............................................... 36 1.8.1 Transcriptional regulation of microRNAs ............................................................ 36 1.8.2 Integrated regulatory network of transcription factors and microRNAs ............ 37 1.9 Genome-wide measurement ...................................................................................... 40 1.9.1 Gene expression .................................................................................................. 40 1.9.2 Proteins in contact with DNA .............................................................................. 41 1.10 Objectives of the research .......................................................................................... 44 Chapter 2: MicroRNA host genes are highly regulated and biased towards developmental functions ..................................................................................................................................... 47 Abstract ................................................................................................................................... 47 2.1 Introduction ................................................................................................................ 48 2.2 Materials and methods ............................................................................................... 51 2.3 Results ......................................................................................................................... 54 2.3.1 MicroRNA host genes are bound by many transcriptional regulators ............... 54 2.3.2 Chromatin modifications to microRNA host genes favour activation of transcription ........................................................................................................................ 54 2.3.3 Expression patterns of intragenic microRNAs and their host genes .................. 57 2.3.4 Characteristics of microRNA host genes ............................................................. 59 2.3.5 MicroRNA host genes are enriched for developmentally important genes ....... 64 2 2.4 Discussion .................................................................................................................... 67 2.5 Conclusions ................................................................................................................. 69 Chapter 3: Coupled regulation of microRNA genes and their protein-coding neighbours ........ 70 Abstract ................................................................................................................................... 70 3.1 Introduction ................................................................................................................ 71 3.2 Methods ...................................................................................................................... 74 3.3 Results ......................................................................................................................... 77 3.3.1 Classification of microRNAs ................................................................................ 77 3.3.2 Intergenic microRNAs are found within regions of high protein-coding gene density……………………………………………………………………………………………………………………………78 3.3.3 MicroRNAs are proximal to protein-coding genes across animal species .......... 80 3.3.4 Favoured orientations of proximal microRNAs ................................................... 81 3.3.5 Comparison between microRNA flanking and host genes………………………………. 84 3.3.6 Cis-regulatory regions of flanking genes ............................................................. 85 3.3.7 Candidate bidirectional promoters of intergenic microRNA and protein-coding gene pairs ............................................................................................................................ 87 3.3.8 Functional association of transcription factors and microRNAs ......................... 88 3.4 Discussion .................................................................................................................... 91 3.5 Conclusions ....................................................................................................................... 93 Chapter 4: Feedforward regulation by transcription factors and microRNAs ............................ 94 Abstract ................................................................................................................................... 94 4.1 Introduction ................................................................................................................ 95 4.2 Methods ...................................................................................................................... 98 4.3 Results ....................................................................................................................... 103 4.3.1 Construction of an integrated regulatory network ........................................... 103 4.3.2 Relationships between TRF- and microRNA-mediated regulation and target gene expression ......................................................................................................................... 106 4.3.3 Bidirectional targeting between a TRF and microRNA pair is linked to TRF regulatory sign .................................................................................................................. 111 4.3.4 Feedforward regulation by TRFs and microRNAs of common gene expression pathways …………………………………………………………………………………………………………………….. 113 4.3.5 Connectivity between TRFs and microRNAs defines gene expression level..... 114 4.3.6 Feedforward circuits are associated with stable mRNA expression levels ....... 116 4.3.7 Feedforward circuits are associated with core cellular processes ................... 118 4.4 Discussion .................................................................................................................. 120 4.5 Conclusions ............................................................................................................... 123 3 Chapter 5: Species-specific gene expression and transcriptional regulation in pathogenic versus natural host SIV infections ........................................................................................................ 124 Abstract ................................................................................................................................. 124 5.1 Introduction .............................................................................................................. 126 5.2 Methods .................................................................................................................... 129 5.3 Results ....................................................................................................................... 132 5.3.1 Gene expression patterns reflect species-specific T cell dynamics ......................... 132 5.3.2 Species-specific patterns of overlap between gene expression clusters ......... 137 5.3.3 Expression changes within peripheral blood CD4+ T cells from individual animals……………………………………………………………………………………………………….…138
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