Gavin Kelsey
Imprinted genes identified
Work in our group stems from screens to identify imprinted genes based on the expectation that imprinted genes would be uniquely identified in the genome because of differences in DNA methylation of the parental alleles. We conducted these screens to learn about the full extent of imprinting in mammals, the classes of genes that have been selected to become imprinted, and whether common mechanisms exist to determine imprinting.
We now know of the existence of some seventy imprinted genes in the mouse genome, many of which are similarly imprinted in humans. We have been using knock-out and transgenic mouse models to investigate the functions of a selection of the imprinted genes we discovered. We are now particularly interested in gaining insights from these genes into the mechanisms by which imprinted genes are marked in the germline.
More information of imprinted genes is available at the MRC Mammalian Genetics Unit website.
Figure 1 (Click to enlarge)
Representation of the mouse karyotype showing imprinted loci identified in methylation-sensitive representational difference analysis (Me-RDA) screens carried out in our group.
Smith et al. (2003) Identification of novel imprinted genes in a genome-wide screen for maternal methylation. Genome Res. 13:558-569.
Establishing imprint marks in germ cells
A fundamental question in imprinting is how such a discrete set of genes is marked in the gametes. A principal component of this marking is DNA methylation at imprinting control regions, but the factors that govern which sequences become methylated in gametes and how differential methylation in male and female gametes is achieved are poorly understood. Very recent work from our lab has uncovered an essential role for transcription in establishment of DNA methylation marks, which we believe applies to all imprinted domains that are marked in the female germline. We are currently seeking to elucidate the mechanistic links between transcription, histone modifications and DNA methylation in germ cells, using a combination of genetic and sensitive molecular approaches. The discovery of a transcriptional component in imprint establishment has profound implications for how imprinted domains evolve and offers new insights into errors that disrupt imprinting and cause imprinted gene syndromes in humans.
Imprinting and optimal adult health
We understand a good deal about the particular roles that imprinted genes have in controlling the growth of the fetus. As an example, we are investigating the function of the Slc38a4 gene, which codes for a transport protein necessary in the developing placenta to ensure efficient transfer of amino acids for the benefit of the growing fetus. The importance of imprinted genes to growth and physiology after birth is also becoming recognised and our work on the imprinted Gnas locus has been particularly informative. We have found that Gnasxl, a gene in this locus that encodes the signalling protein XLαs, plays a major part in adaptations to postnatal life and to the control of energy balance. Lack of this gene causes a lifelong lean and hypermetabolic phenotype, and it appears that XLαs regulates energy balance by effects within adipose tissues as well as by controlling sympathetic activity towards adipose. Other examples show how proper control of imprinted gene expression is vital: two-fold over-expression of the imprinted gene ZAC1 perturbs normal pancreatic development and may cause diabetes in infants. Arising from such findings, we are investigating the possibility that optimal expression of imprinted genes is an important factor in programming of optimal adult health, and whether these genes are vulnerable to adverse environmental or nutritional influence
Figure 2. Immunofluorescence for the imprinted signalling protein XLαs in the arcuate nucleus of the hypothalamus. XLαs is localised as red signals; |
Chotalia M, Smallwood S, Ruf N, Dawson C, Lucifero D, Frontera M, James K, Dean WL, Kelsey GD (2009) Transcription is required for establishment of germline methylation marks at imprinted genes.
Genes and Development 23 105-117
http://dx.doi.org/10.1101/gad.495809
Ruf N, Bahring S, Galetzka D, Pliushch G, Luft FC, Nurnberg P, Haaf T, Kelsey GD, Zechner U (2007) Sequence-based bioinformatic prediction and QUASEP identify genomic imprinting of the KCNK9 potassium channel gene in mouse and human.
Human and Molecular Genetics 16 2591-2599
http://dx.doi.org/10.1093/hmg/ddm216
Arnaud P, Hata K, Kaneda M, Li E, Sasaki H, Feil R, Kelsey GD (2006) Stochastic imprinting in the progeny of Dnmt3L-/- females.
Human Molecular Genetics 15 589-598
http://dx.doi.org/10.1093/hmg/ddi475
Williamson CM, Turner MD, Ball ST, Nottingham WT, Glenister P, Fray M, Tymowska-Lalanne Z, Plagge A, Powles-Glover N, Kelsey GD, Maconochie M, Peters J (2006) Identification of an imprinting control region affecting the expression of all transcripts in the Gnas cluster.
Nature Genetics 38 350-355
http://dx.doi.org/10.1038/ng1731
Xie T, Plagge A, Gavrilova O, Pack S, Jou W, Lai EW, Frontera M, Kelsey GD, Weinstein LS (2006) The alternative stimulatory G protein α-subunit XLαs is a critical regulator of energy and glucose metabolism and sympathetic nerve activity in adult mice.
Journal of Biological Chemistry 281 18989-18999
http://dx.doi.org/10.1074/jbc.M511752200
Plagge A, Isles AR, Gordon E, Humby T, Dean WL, Gritsch S, Fischer-Colbrie R, Wilkinson LS, Kelsey GD (2005) Imprinted Nesp55 influences behavioral reactivity to novel environments.
Molecular and Cellular Biology 25 3019-3026
http://dx.doi.org/10.1128/MCB.25.8.3019-3026.2005
Ma D, Shield JPH, Dean WL, Leclerc I, Knauf C, Burcelin R, Rutter GA, Kelsey GD (2004) Impaired glucose homeostasis in transgenic mice expressing the human transient neonatal diabetes mellitus locus, TNDM.
Journal of Clinical Investigation 114 339-348
http://dx.doi.org/10.1172/JCI200419876
Plagge A, Gordon E, Dean WL, Boiani R, Cinti S, Peters J, Kelsey GD (2004) The imprinted signalling protein XLαs is required for postnatal adaptation to feeding.
Nature Genetics 36 818-826
http://dx.doi.org/10.1038/ng1397
Coombes C, Arnaud P, Gordon E, Dean WL, Coar EA, Williamson CM, Feil R, Peters J, Kelsey GD (2003) Epigenetic properties and identification of an imprint mark in the Nesp-Gnasxl domain of the mouse Gnas imprinted locus.
Molecular and Cellular Biology 23 5475-5488
http://dx.doi.org/10.1128/MCB.23.16.5475-5488.2003
Smith RJ, Dean WL, Konfortova G, Kelsey GD (2003) Identification of novel imprinted genes in a genome-wide screen for maternal methylation.
Genome Research 13 558-569
http://dx.doi.org/10.1101/gr.781503
