Skip to main content Accessibility help

The noncoding human genome and the future of personalised medicine

  • Philip Cowie (a1), Elizabeth A. Hay (a1) and Alasdair MacKenzie (a1)


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.


Corresponding author

* Corresponding author: Alasdair MacKenzie, University of Aberdeen, School of Medical Sciences, Foresterhill, Aberdeen, AB25 2ZD, United Kingdom. E-mail


Hide All
1 Maurano, M.T. et al. (2012) Systematic localization of common disease-associated variation in regulatory DNA. Science 337, 1190-1195
2 Dunham, I. et al. (2012) An integrated encyclopedia of DNA elements in the human genome. Nature 489, 57-74
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
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
5 Lenhard, B., Sandelin, A. and Carninci, P. (2012) Metazoan promoters: emerging characteristics and insights into transcriptional regulation. Nature Review Genetics 13, 233-245
6 Bannister, A.J. and Kouzarides, T. (2011) Regulation of chromatin by histone modifications. Cell Research 21, 381-395
7 Jin, B. and Robertson, K.D. (2012) DNA methyltransferases, DNA damage repair, and cancer. Advances in Experimental Medicine and Biology 754, 3-29
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
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
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
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
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
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
14 Sanyal, A. et al. (2012) The long-range interaction landscape of gene promoters. Nature 489, 109-113
15 Wasserman, W.W. and Sandelin, A. (2004) Applied bioinformatics for the identification of regulatory elements. Nature Review Genetics 5, 276-287
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
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
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
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
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
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
22 Visel, A., Bristow, J. and Pennacchio, L.A. (2007) Enhancer identification through comparative genomics. Seminars Cell and Developmental Biology 18, 140-152
23 Odom, D.T. et al. (2007) Tissue-specific transcriptional regulation has diverged significantly between human and mouse. Nature Genetics 39, 730-732
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
25 Visel, A. et al. (2009) ChIP-seq accurately predicts tissue-specific activity of enhancers. Nature 457, 854-858
26 Visel, A., Rubin, E.M. and Pennacchio, L.A. (2009) Genomic views of distant-acting enhancers. Nature 461, 199-205
27 Andersson, R. et al. (2014) An atlas of active enhancers across human cell types and tissues. Nature 507, 455-461
28 Calo, E. and Wysocka, J. (2013) Modification of enhancer chromatin: what, how, and why? Molecular Cell 49, 825-837
29 Attanasio, C. et al. (2013) Fine tuning of craniofacial morphology by distant-acting enhancers. Science 342, 1241006
30 Barski, A. and Zhao, K. (2009) Genomic location analysis by ChIP-Seq. Journal of Cell Biochemistry 107, 11-18
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
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
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
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
35 Schwartz, Y.B. and Pirrotta, V. (2013) A new world of Polycombs: unexpected partnerships and emerging functions. Nature Review Genetics 14, 853-864
36 Kolovos, P. et al. (2012) Enhancers and silencers: an integrated and simple model for their function. Epigenetics Chromatin 5, 1
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
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
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
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
41 de Wit, E. and de Laat, W. (2012) A decade of 3C technologies: insights into nuclear organization. Genes Development 26, 11-24
42 Chetverina, D. et al. (2014) Making connections: insulators organize eukaryotic chromosomes into independent cis-regulatory networks. Bioessays 36, 163-172
43 Symmons, O. et al. (2014) Functional and topological characteristics of mammalian regulatory domains. Genome Research 24, 390-400
44 Papantonis, A. and Cook, P.R. (2013) Transcription factories: genome organization and gene regulation. Chemical Reviews 113, 8683-8705
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
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
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
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
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
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
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
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
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
54 Emison, E.S. et al. (2005) A common sex-dependent mutation in a RET enhancer underlies Hirschsprung disease risk. Nature 434, 857-863
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
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
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
58 Juhasz, G. et al. (2011) The CREB1-BDNF-NTRK2 pathway in depression: multiple gene-cognition-environment interactions. Biological Psychiatry 69, 762-771
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
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
61 Ficz, G. et al. (2011) Dynamic regulation of 5-hydroxymethylcytosine in mouse ES cells and during differentiation. Nature 473, 398-402
62 Booth, M.J. et al. (2013) Oxidative bisulfite sequencing of 5-methylcytosine and 5-hydroxymethylcytosine. Nature Protocol 8, 1841-1851
63 Schmitt, A. et al. (2014) The impact of environmental factors in severe psychiatric disorders. Frontier in Neuroscience 8, 19
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
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
66 Drummond, E.M. and Gibney, E.R. (2013) Epigenetic regulation in obesity. Current Opinion Clinical Nutrition Metabolic Care 16, 392-397
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
68 Murgatroyd, C. et al. (2009) Dynamic DNA methylation programs persistent adverse effects of early-life stress. Nature Neuroscience 12, 1559-1566
69 Murgatroyd, C. et al. (2010) Genes learn from stress: how infantile trauma programs us for depression. Epigenetics 5(3), 194-199
70 Nephew, B. and Murgatroyd, C. (2013) The role of maternal care in shaping CNS function. Neuropeptides 47, 371-378
71 Murgatroyd, C. and Spengler, D. (2012) Epigenetic programming of the HPA axis: early life decides. Stress 14, 581-589
72 Murgatroyd, C. and Spengler, D. (2011) Epigenetics of early child development. Frontiers in Psychiatry 2, 16
73 Menger, Y. et al. (2011) Sex differences in brain epigenetics. Epigenomics 2, 807-821
74 Bettscheider, M., Murgatroyd, C. and Spengler, D. (2011) Simultaneous DNA and RNA isolation from brain punches for epigenetics. BMC Research Notes 4, 314
75 Murgatroyd, C. et al. (2010) The Janus face of DNA methylation in aging. Aging (Albany NY) 2, 107-110
76 Murgatroyd, C. and Spengler, D. (2010) Histone tales: echoes from the past, prospects for the future. Genome Biology 11, 105
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
78 Heller, F. (2013) Genetics/genomics and drug effects. Acta Clinica Belgica 68, 77-80
79 Lanni, C., Racchi, M. and Govoni, S. (2013) Do we need pharmacogenetics to personalize antidepressant therapy? Cell Molecular Life Science 70, 3327-3340
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
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
82 Singh, P., Schimenti, J.C. and Bolcun-Filas, E. (2014) A mouse geneticist's practical guide to CRISPR Applications. Genetics (in Press)

UCSC genome browser

Human Genome Navigator

Maurano, M. T., et al. (2012). Systematic localization of common disease-associated variation in regulatory DNA. Science 337(6099): 1190-5.
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.
Murgatroyd, C. and Spengler, D. (2012). Epigenetic programming of the HPA axis: early life decides. Stress 14(6): 581.
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.

Related content

Powered by UNSILO

The noncoding human genome and the future of personalised medicine

  • Philip Cowie (a1), Elizabeth A. Hay (a1) and Alasdair MacKenzie (a1)


Altmetric attention score

Full text views

Total number of HTML views: 0
Total number of PDF views: 0 *
Loading metrics...

Abstract views

Total abstract views: 0 *
Loading metrics...

* Views captured on Cambridge Core between <date>. This data will be updated every 24 hours.

Usage data cannot currently be displayed.