Highlight Publication January 2009

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

Lay summary

We inherit similar sets of genes from our fathers and mothers and, for the most part, the copies we receive from either parent are equally active.  An intriguing exception to this general rule occurs in a process called genomic imprinting, in which one copy of some of our genes is deliberately silenced.  These so-called imprinted genes are particularly important in determining how the foetus grows and how infants adapt their physiology to life outside the womb.  But the fact that these genes have one copy pre-determined to be silent makes them particularly vulnerable to mutation events, such that imprinted gene defects are a cause of disease and some cancers.

Imprinted genes behave in this manner because they are marked in different ways in the male and female germ cells.  These imprint marks comprise a chemical modification called DNA methylation, but what specifies which sequences receive these marks is poorly understood.

In this article, we have identified an important and surprising component of the mechanism that targets DNA methylation to imprinted genes in female germ cells.  We have discovered that the imprinted sequences need to be active during the critical time window in egg development to make them accessible to the molecular machinery responsible for adding methylation to the DNA.  This is an unexpected new twist in the relationship between gene activity and DNA methylation, as methylation is more commonly thought of in association with gene inactivity.

Insights gained from this work will help to explain the causes of imprinted gene disorders and, possibly, some of the abnormalities associated with assisted reproduction technologies.  They also suggest new explanations for other abnormal methylation events, such as the silencing of tumour suppressor genes in cancer.

Continuation of this work is supported by a recently awarded grant from the MRC.

Lead author

Mita Chotalia obtained her first degree from the University of Manchester Institute of Science and Technology and joined Gavin Kelsey’s lab as a Ph. D. student in October 2004, supported by a studentship from the BBSRC under the Integrated Epigenetics Initiative.  Her Ph.D., which she completed in 2008, investigated mechanisms by which DNA methylation is established at the sequences that control the imprinting of genes.  Mita has now taken up a post-doctoral position in the Nuclear Organisation Group at the MRC Clinical Sciences Centre, London.