Hostname: page-component-745bb68f8f-cphqk Total loading time: 0 Render date: 2025-01-18T19:21:35.714Z Has data issue: false hasContentIssue false
  • English
  • Français

The noncoding human genome and the future of personalised medicine

Published online by Cambridge University Press:  30 January 2015

Philip Cowie ,
Elizabeth A. Hay  and
Alasdair MacKenzie
Philip Cowie
Affiliation:
The School of Medical Sciences, Institute of Medical Sciences, University of Aberdeen, Foresterhill, Aberdeen AB25 2ZD, UK.
Elizabeth A. Hay
Affiliation:
The School of Medical Sciences, Institute of Medical Sciences, University of Aberdeen, Foresterhill, Aberdeen AB25 2ZD, UK.
Alasdair MacKenzie*
Affiliation:
The School of Medical Sciences, Institute of Medical Sciences, University of Aberdeen, Foresterhill, Aberdeen AB25 2ZD, UK.
*
*Corresponding author: Alasdair MacKenzie, University of Aberdeen, School of Medical Sciences, Foresterhill, Aberdeen, AB25 2ZD, United Kingdom. E-mail [email protected]
Get access Rights & Permissions [Opens in a new window]

Abstract

Non-coding cis-regulatory sequences act as the ‘eyes’ of the genome and their role is to perceive, organise and relay cellular communication information to RNA polymerase II at gene promoters. The evolution of these sequences, that include enhancers, silencers, insulators and promoters, has progressed in multicellular organisms to the extent that cis-regulatory sequences make up as much as 10% of the human genome. Parallel evidence suggests that 75% of polymorphisms associated with heritable disease occur within predicted cis-regulatory sequences that effectively alter the ‘perception’ of cis-regulatory sequences or render them blind to cell communication cues. Cis-regulatory sequences also act as major functional targets of epigenetic modification thus representing an important conduit through which changes in DNA-methylation affects disease susceptibility. The objectives of the current review are (1) to describe what has been learned about identifying and characterising cis-regulatory sequences since the sequencing of the human genome; (2) to discuss their role in interpreting cell signalling pathways pathways; and (3) outline how this role may be altered by polymorphisms and epigenetic changes. We argue that the importance of the cis-regulatory genome for the interpretation of cellular communication pathways cannot be overstated and understanding its role in health and disease will be critical for the future development of personalised medicine.

Type
Review Article
Information
Expert Reviews in Molecular Medicine , Volume 17 , 2015 , e4
Copyright
Copyright © Cambridge University Press 2015 

Access options

Get access to the full version of this content by using one of the access options below. (Log in options will check for institutional or personal access. Content may require purchase if you do not have access.)

References

References

1 Maurano, M.T. et al. (2012) Systematic localization of common disease-associated variation in regulatory DNA. Science 337, 1190-1195 CrossRefGoogle ScholarPubMed
2 Dunham, I. et al. (2012) An integrated encyclopedia of DNA elements in the human genome. Nature 489, 57-74 Google Scholar
3 Graur, D. et al. (2013) On the immortality of television sets: ‘function’ in the human genome according to the evolution-free gospel of ENCODE. Genome Biology Evolution 5, 578-590 Google Scholar
4 MacKenzie, A., Hing, B. and Davidson, S. (2013) Exploring the effects of polymorphisms on cis-regulatory signal transduction response. Trends in Molecular Medicine 19, 99-107 CrossRefGoogle ScholarPubMed
5 Lenhard, B., Sandelin, A. and Carninci, P. (2012) Metazoan promoters: emerging characteristics and insights into transcriptional regulation. Nature Review Genetics 13, 233-245 CrossRefGoogle ScholarPubMed
6 Bannister, A.J. and Kouzarides, T. (2011) Regulation of chromatin by histone modifications. Cell Research 21, 381-395 CrossRefGoogle ScholarPubMed
7 Jin, B. and Robertson, K.D. (2012) DNA methyltransferases, DNA damage repair, and cancer. Advances in Experimental Medicine and Biology 754, 3-29 CrossRefGoogle Scholar
8 Long, H.K. et al. (2013) Epigenetic conservation at gene regulatory elements revealed by non-methylated DNA profiling in seven vertebrates. Elife 2, e00348 CrossRefGoogle ScholarPubMed
9 Ginno, P.A. et al. (2012) R-loop formation is a distinctive characteristic of unmethylated human CpG island promoters. Molecular Cell 45, 814-825 CrossRefGoogle ScholarPubMed
10 van Otterdijk, S.D., Mathers, J.C. and Strathdee, G. (2013) Do age-related changes in DNA methylation play a role in the development of age-related diseases? Biochemical Society Transactions 41, 803-807 CrossRefGoogle ScholarPubMed
11 Anier, K. et al. (2013) Maternal separation is associated with DNA methylation and behavioural changes in adult rats. European Neuropsychopharmacology 24(3), 459-468 CrossRefGoogle ScholarPubMed
12 Kang, H.J. et al. (2013) Association of SLC6A4 methylation with early adversity, characteristics and outcomes in depression. Progress in Neuropsychopharmacology Biology Psychiatry 44, 23-28 CrossRefGoogle ScholarPubMed
13 Ouellet-Morin, I. et al. (2012) Increased serotonin transporter gene (SERT) DNA methylation is associated with bullying victimization and blunted cortisol response to stress in childhood: a longitudinal study of discordant monozygotic twins. Psychological Medicine 43, 1813-1823 CrossRefGoogle ScholarPubMed
14 Sanyal, A. et al. (2012) The long-range interaction landscape of gene promoters. Nature 489, 109-113 CrossRefGoogle ScholarPubMed
15 Wasserman, W.W. and Sandelin, A. (2004) Applied bioinformatics for the identification of regulatory elements. Nature Review Genetics 5, 276-287 CrossRefGoogle ScholarPubMed
16 de Villiers, J. and Schaffner, W. (1981) A small segment of polyoma virus DNA enhances the expression of a cloned beta-globin gene over a distance of 1400 base pairs. Nucleic Acids Research 9, 6251-6264 CrossRefGoogle Scholar
17 Veldman, G.M., Lupton, S. and Kamen, R. (1985) Polyomavirus enhancer contains multiple redundant sequence elements that activate both DNA replication and gene expression. Molecular and Cell Biology 5, 649-658 Google ScholarPubMed
18 MacKenzie, A. et al. (1997) Two enhancer domains control early aspects of the complex expression pattern of Msx1. Mechanisms of Development 62, 29-40 CrossRefGoogle ScholarPubMed
19 Marinic, M. et al. (2013) An integrated holo-enhancer unit defines tissue and gene specificity of the Fgf8 regulatory landscape. Developmental Cell 24, 530-542 CrossRefGoogle ScholarPubMed
20 Loots, G.G. et al. (2000) Identification of a coordinate regulator of interleukins 4, 13, and 5 by cross-species sequence comparisons. Science 288, 136-140 CrossRefGoogle Scholar
21 Miller, K.A. et al. (2007) A highly conserved Wnt-dependent TCF4 binding site within the proximal enhancer of the anti-myogenic Msx1 gene supports expression within Pax3-expressing limb bud muscle precursor cells. Developmental Biology 311, 665-678 CrossRefGoogle ScholarPubMed
22 Visel, A., Bristow, J. and Pennacchio, L.A. (2007) Enhancer identification through comparative genomics. Seminars Cell and Developmental Biology 18, 140-152 CrossRefGoogle ScholarPubMed
23 Odom, D.T. et al. (2007) Tissue-specific transcriptional regulation has diverged significantly between human and mouse. Nature Genetics 39, 730-732 CrossRefGoogle ScholarPubMed
24 Birney, E. et al. (2007) Identification and analysis of functional elements in 1% of the human genome by the ENCODE pilot project. Nature 447, 799-816 Google ScholarPubMed
25 Visel, A. et al. (2009) ChIP-seq accurately predicts tissue-specific activity of enhancers. Nature 457, 854-858 CrossRefGoogle ScholarPubMed
26 Visel, A., Rubin, E.M. and Pennacchio, L.A. (2009) Genomic views of distant-acting enhancers. Nature 461, 199-205 CrossRefGoogle ScholarPubMed
27 Andersson, R. et al. (2014) An atlas of active enhancers across human cell types and tissues. Nature 507, 455-461 CrossRefGoogle ScholarPubMed
28 Calo, E. and Wysocka, J. (2013) Modification of enhancer chromatin: what, how, and why? Molecular Cell 49, 825-837 CrossRefGoogle ScholarPubMed
29 Attanasio, C. et al. (2013) Fine tuning of craniofacial morphology by distant-acting enhancers. Science 342, 1241006 CrossRefGoogle ScholarPubMed
30 Barski, A. and Zhao, K. (2009) Genomic location analysis by ChIP-Seq. Journal of Cell Biochemistry 107, 11-18 CrossRefGoogle ScholarPubMed
31 Furey, T.S. (2012) ChIP-seq and beyond: new and improved methodologies to detect and characterize protein-DNA interactions. Nature Reviews Genetics 13, 840-852 CrossRefGoogle ScholarPubMed
32 Song, L. et al. (2011) Open chromatin defined by DNaseI and FAIRE identifies regulatory elements that shape cell-type identity. Genome Research 21, 1757-1767 CrossRefGoogle ScholarPubMed
33 Nagy, P.L. and Price, D.H. (2009) Formaldehyde-assisted isolation of regulatory elements. Wiley Interdisciplinary Reviews: Systems Biology and Medicine 1, 400-406 Google ScholarPubMed
34 Zuccato, C. et al. (2007) Widespread disruption of repressor element-1 silencing transcription factor/neuron-restrictive silencer factor occupancy at its target genes in Huntington's disease. Journal of Neuroscience 27, 6972-6983 CrossRefGoogle ScholarPubMed
35 Schwartz, Y.B. and Pirrotta, V. (2013) A new world of Polycombs: unexpected partnerships and emerging functions. Nature Review Genetics 14, 853-864 CrossRefGoogle ScholarPubMed
36 Kolovos, P. et al. (2012) Enhancers and silencers: an integrated and simple model for their function. Epigenetics Chromatin 5, 1 CrossRefGoogle ScholarPubMed
37 Lettice, L.A. et al. (2008) Point mutations in a distant sonic hedgehog cis-regulator generate a variable regulatory output responsible for preaxial polydactyly. Human Molecular Genetics 17, 978-985 CrossRefGoogle Scholar
38 Lettice, L.A. et al. (2002) Disruption of a long-range cis-acting regulator for Shh causes preaxial polydactyly. Proceedings of National Academy Science of the United States of America 99, 7548-7553 CrossRefGoogle ScholarPubMed
39 Davidson, S. et al. (2006) A remote and highly conserved enhancer supports amygdala specific expression of the gene encoding the anxiogenic neuropeptide substance-P. Molecular Psychiatry 11, 410-421 CrossRefGoogle ScholarPubMed
40 Shanley, L. et al. (2010) Long-range regulatory synergy is required to allow control of the TAC1 locus by MEK/ERK signalling in sensory neurones. Neurosignals 18, 173-185 CrossRefGoogle ScholarPubMed
41 de Wit, E. and de Laat, W. (2012) A decade of 3C technologies: insights into nuclear organization. Genes Development 26, 11-24 Google ScholarPubMed
42 Chetverina, D. et al. (2014) Making connections: insulators organize eukaryotic chromosomes into independent cis-regulatory networks. Bioessays 36, 163-172 CrossRefGoogle ScholarPubMed
43 Symmons, O. et al. (2014) Functional and topological characteristics of mammalian regulatory domains. Genome Research 24, 390-400 CrossRefGoogle ScholarPubMed
44 Papantonis, A. and Cook, P.R. (2013) Transcription factories: genome organization and gene regulation. Chemical Reviews 113, 8683-8705 CrossRefGoogle ScholarPubMed
45 de Villiers, J. et al. (1982) Transcriptional ‘enhancers’ from SV40 and polyoma virus show a cell type preference. Nucleic Acids Research 10, 7965-7976 CrossRefGoogle ScholarPubMed
46 Miller, K.A. et al. (2008) Prediction and characterisation of a highly conserved, remote and cAMP responsive enhancer that regulates Msx1 gene expression in cardiac neural crest and outflow tract. Developmental Biology 317, 686-694 CrossRefGoogle ScholarPubMed
47 Consortium, I.C.G.S. (2004) Sequence and comparative analysis of the chicken genome provide unique perspectives on vertebrate evolution. Nature 432, 695-716 Google Scholar
48 Davidson, S. et al. (2006) Cellular co-expression of a LacZ marker gene driven by the amygdala-specific ECR1 enhancer with the substance P neuropeptide. Molecular Psychiatry 11, 323 CrossRefGoogle Scholar
49 Ebner, K. et al. (2008) Substance P in stress and anxiety: NK-1 receptor antagonism interacts with key brain areas of the stress circuitry. Annals of the New York Academy of Sciences 1144, 61-73 CrossRefGoogle ScholarPubMed
50 Shanley, L. et al. (2011) Evidence for regulatory diversity and auto-regulation at the TAC1 locus in sensory neurones. Journal of Neuroinflammation 8, 10 CrossRefGoogle ScholarPubMed
51 Lettice, L., Heaney, S. and Hill, R. (2002) 2 Preaxial polydactyly in human and mouse: regulatory anomalies in digit patterning. Journal of Anatomy 201, 417 Google ScholarPubMed
52 Lettice, L.A. and Hill, R.E. (2005) Preaxial polydactyly: a model for defective long-range regulation in congenital abnormalities. Current Opinion in Genetics and Development 15, 294-300 CrossRefGoogle Scholar
53 Lettice, L.A. et al. (2003) A long-range Shh enhancer regulates expression in the developing limb and fin and is associated with preaxial polydactyly. Human Molecular Genetics 12, 1725-1735 CrossRefGoogle ScholarPubMed
54 Emison, E.S. et al. (2005) A common sex-dependent mutation in a RET enhancer underlies Hirschsprung disease risk. Nature 434, 857-863 CrossRefGoogle Scholar
55 Ombrello, M.J., Sikora, K.A. and Kastner, D.L. (2014) Genetics, genomics, and their relevance to pathology and therapy. Best Practice and Research Clinical Rheumatology 28, 175-189 CrossRefGoogle Scholar
56 Davidson, S. et al. (2011) Differential activity by polymorphic variants of a remote enhancer that supports galanin expression in the hypothalamus and amygdala: implications for obesity, depression and alcoholism. Neuropsychopharmacology 36, 2211-2221 CrossRefGoogle ScholarPubMed
57 Nikolova, Y.S. et al. (2013) Reward-related ventral striatum reactivity mediates gender-specific effects of a galanin remote enhancer haplotype on problem drinking. Genes Brain Behaviour 12, 516-524 CrossRefGoogle ScholarPubMed
58 Juhasz, G. et al. (2011) The CREB1-BDNF-NTRK2 pathway in depression: multiple gene-cognition-environment interactions. Biological Psychiatry 69, 762-771 CrossRefGoogle ScholarPubMed
59 Hing, B. et al. (2012) A polymorphism associated with depressive disorders differentially regulates brain derived neurotrophic factor promoter IV activity. Biological Psychiatry 71, 618-626 CrossRefGoogle ScholarPubMed
60 Branco, M.R., Ficz, G. and Reik, W. (2011) Uncovering the role of 5-hydroxymethylcytosine in the epigenome. Nature Review of Genetics 13, 7-13 CrossRefGoogle ScholarPubMed
61 Ficz, G. et al. (2011) Dynamic regulation of 5-hydroxymethylcytosine in mouse ES cells and during differentiation. Nature 473, 398-402 CrossRefGoogle ScholarPubMed
62 Booth, M.J. et al. (2013) Oxidative bisulfite sequencing of 5-methylcytosine and 5-hydroxymethylcytosine. Nature Protocol 8, 1841-1851 CrossRefGoogle ScholarPubMed
63 Schmitt, A. et al. (2014) The impact of environmental factors in severe psychiatric disorders. Frontier in Neuroscience 8, 19 Google ScholarPubMed
64 Tarry-Adkins, J.L. and Ozanne, S.E. (2014) The impact of early nutrition on the ageing trajectory. Proceedings of the Nutrition Society 73(2), 289-301 CrossRefGoogle ScholarPubMed
65 Glier, M.B., Green, T.J. and Devlin, A.M. (2013) Methyl nutrients, DNA methylation, and cardiovascular disease. Molecular Nutrition Food Research 58, 172-182 CrossRefGoogle ScholarPubMed
66 Drummond, E.M. and Gibney, E.R. (2013) Epigenetic regulation in obesity. Current Opinion Clinical Nutrition Metabolic Care 16, 392-397 Google ScholarPubMed
67 Dalton, V.S., Kolshus, E. and McLoughlin, D.M. (2013) Epigenetics and depression: return of the repressed. Journal of Affect Disorder 155, 1-12 CrossRefGoogle ScholarPubMed
68 Murgatroyd, C. et al. (2009) Dynamic DNA methylation programs persistent adverse effects of early-life stress. Nature Neuroscience 12, 1559-1566 CrossRefGoogle ScholarPubMed
69 Murgatroyd, C. et al. (2010) Genes learn from stress: how infantile trauma programs us for depression. Epigenetics 5(3), 194-199 CrossRefGoogle ScholarPubMed
70 Nephew, B. and Murgatroyd, C. (2013) The role of maternal care in shaping CNS function. Neuropeptides 47, 371-378 CrossRefGoogle ScholarPubMed
71 Murgatroyd, C. and Spengler, D. (2012) Epigenetic programming of the HPA axis: early life decides. Stress 14, 581-589 CrossRefGoogle Scholar
72 Murgatroyd, C. and Spengler, D. (2011) Epigenetics of early child development. Frontiers in Psychiatry 2, 16 CrossRefGoogle ScholarPubMed
73 Menger, Y. et al. (2011) Sex differences in brain epigenetics. Epigenomics 2, 807-821 CrossRefGoogle Scholar
74 Bettscheider, M., Murgatroyd, C. and Spengler, D. (2011) Simultaneous DNA and RNA isolation from brain punches for epigenetics. BMC Research Notes 4, 314 CrossRefGoogle ScholarPubMed
75 Murgatroyd, C. et al. (2010) The Janus face of DNA methylation in aging. Aging (Albany NY) 2, 107-110 CrossRefGoogle ScholarPubMed
76 Murgatroyd, C. and Spengler, D. (2010) Histone tales: echoes from the past, prospects for the future. Genome Biology 11, 105 CrossRefGoogle ScholarPubMed
77 Nicoll, G. et al. (2012) Allele-specific differences in activity of a novel cannabinoid receptor 1 (CNR1) gene intronic enhancer in hypothalamus, dorsal root ganglia, and hippocampus. Journal of Biological Chemistry 287, 12828-12834 CrossRefGoogle ScholarPubMed
78 Heller, F. (2013) Genetics/genomics and drug effects. Acta Clinica Belgica 68, 77-80 CrossRefGoogle ScholarPubMed
79 Lanni, C., Racchi, M. and Govoni, S. (2013) Do we need pharmacogenetics to personalize antidepressant therapy? Cell Molecular Life Science 70, 3327-3340 CrossRefGoogle ScholarPubMed
80 Kangas, B.D. et al. (2013) Cannabinoid discrimination and antagonism by CB(1) neutral and inverse agonist antagonists. Journal of Pharmacology Experimental Therapeutics 344, 561-567 CrossRefGoogle ScholarPubMed
81 Gaj, T., Gersbach, C.A. and Barbas, C.F. 3rd (2013) ZFN, TALEN, and CRISPR/Cas-based methods for genome engineering. Trends in Biotechnology 31, 397-405 CrossRefGoogle ScholarPubMed
82 Singh, P., Schimenti, J.C. and Bolcun-Filas, E. (2014) A mouse geneticist's practical guide to CRISPR Applications. Genetics (in Press)Google ScholarPubMed

Further reading, resources and contacts

UCSC genome browser

http://genome.ucsc.edu/.

Human Genome Navigator

http://hugenavigator.net/HuGENavigator/home.do.

Maurano, M. T., et al. (2012). Systematic localization of common disease-associated variation in regulatory DNA. Science 337(6099): 1190-5.CrossRefGoogle ScholarPubMed
Graur, D., et al. (2013). On the immortality of television sets: “function” in the human genome according to the evolution-free gospel of ENCODE. Genome Biol Evol 5(3): 578-90.CrossRefGoogle Scholar
Murgatroyd, C. and Spengler, D. (2012). Epigenetic programming of the HPA axis: early life decides. Stress 14(6): 581.CrossRefGoogle Scholar
MacKenzie, A., Hing, B. and Davidson, S. (2013). Exploring the effects of polymorphisms on cis-regulatory signal transduction response. Trends Mol Med 19(2): 99-107.CrossRefGoogle ScholarPubMed
Maurano, M. T., et al. (2012). Systematic localization of common disease-associated variation in regulatory DNA. Science 337(6099): 1190-5.CrossRefGoogle ScholarPubMed
Graur, D., et al. (2013). On the immortality of television sets: “function” in the human genome according to the evolution-free gospel of ENCODE. Genome Biol Evol 5(3): 578-90.CrossRefGoogle Scholar
Murgatroyd, C. and Spengler, D. (2012). Epigenetic programming of the HPA axis: early life decides. Stress 14(6): 581.CrossRefGoogle Scholar
MacKenzie, A., Hing, B. and Davidson, S. (2013). Exploring the effects of polymorphisms on cis-regulatory signal transduction response. Trends Mol Med 19(2): 99-107.CrossRefGoogle ScholarPubMed