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Mammalian Genetics » Research |
| Mammalian Genetics |
| Overview of Research Interests |
The fusion of two haploid cells (a sperm and an egg) to produce the diploid zygote heralds the development of a new organism. According to Mendel's laws of inheritance the genetic information contributed by the sperm (from the father) and the egg (from the mother) is equal. This would in effect mean that given the right conditions, fusion of two sperm nuclei or two egg nuclei should lead to normal development of an organism. However, this was found not to be the case in mammals. In a series of elegent nuclear transfer experiments done in early 1980's it was found that mouse embryos with two paternal copies (androgenetic) or two maternal copies (parthenogenetic) of the genome died very early in embryonic development. Moreover, their development was different not only from a normal biparental embryo but also from each other. Therefore in mammals, maternal and paternal contribution to the progeny is not equal and for normal development contribution from both parents is required. The reason for this non-equivalence is the presence of certain genes with the mammalian genome which are expressed from the maternally or paternally inherited allele. These genes are called imprinted genes and this phenomenon of non-equivalence of the parental genomes is termed as genomic imprinting. Our laboratory is interested in finding out the mechanisms by which this non-equivalence of the two parental genomes is achieved and maintained.
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Projects
Chromatin organisation and genomic imprinting :
For imprinted genes one copy of a DNA molecule is transcribed and the other copy is silent. What distinguishes two molecules of the same DNA sequence within the same nucleus? The answer lies not in the genetic information encoded by the DNA sequence but in its epigenetic modifications. These modifications include differential modification of the DNA itself and differential organisation of DNA within the chromatin scaffold. One important modification of DNA known in mammals is methylation of cytosine residues in the CpG dinucleotides. However, methylation does not answer all mechanistic questions related to imprinted genes. If one allele of a gene becomes methylated what prevents methylation of the other allele? Does the unmethylated allele carry another epigenetic imprint? To investigate the mechanisms of genomic imprinting , it would therefore be essential to identify the alternative imprint on the unmethylated allele. Recently it has been found that within the differentially methylated regions of some imprinted genes there are sub-regions that also show differential organisation of chromatin. Interestingly, the regions which show differential chromatin organisation have also been genetically defined as Imprinting Control Regions (ICRs) and shown to control the imprinting status of genes within that locus. In all the imprinted loci analysed, specialised chromatin structures were found exclusively on the unmethylated allele. This suggests that for these regions, methylation and specialised chromatin structures are mutually exclusive and reflects alternate epigenetic states. How is this mutual exclusiveness between methylation and specialised chromatin structures maintained? Do the chromatin modifications on unmethylated allele prevent it from getting methylated? More importantly, during development when are these chromatin structures established? Can such chromatin conformations behave as imprints marking the parental alleles? The aim of the ongoing project is to answer these questions and identify the role of chromatin organisation in mechanisms underlying genomic imprinting in particular and as a epigenetic regulator of gene expression in general. |
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| Last updated on: 7th May, 2009. |
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