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The role of imprinted genes in mouse models of IUGR

University of British Columbia

Each year in Canada, 5% of ongoing pregnancies are affected by intrauterine growth restriction (IUGR), a condition diagnosed when a baby's birth weight is less than the bottom 5th percentile. Placental dysfunction is thought to be the main contributor to IUGR and many genetic aberrations can lead to problems in the placenta. The epigenetic phenomenon, genomic imprinting, has evolved with placentation and gene knockout studies of several imprinted genes in the mouse result in IUGR. The main goal of this thesis is to examine how gene expression of all imprinted genes is affected in mouse models of IUGR (Mmp2-/-, Mest+/- and Surgical). The first step is to find suitable IUGR mouse models by comparing the embryonic weights of potential models to normal mouse embryos. Next, I assessed gene expression using genome-wide assays and looked at how expression of imprinted genes is altered in the IUGR mouse model. Amongst the three models, only the surgical model was identified as having IUGR and RNA samples from this model were used in genome-wide expression assays. We found 68 candidate IUGR genes, 42 genes had a 2-fold difference in IUGR embryos or placentae, with 26 genes altered in both tissue. Genes that function in the transport of substances are the most altered in both tissue. The genes that are involved in the development of anatomical structures were affected more in the IUGR embryos whilst stress response genes were more affected in the IUGR placentae. For imprinted genes, only 4 genes in the embryo (H19, Igf2, Slc38a4, and Dlk1) and 6 genes in the placenta (Slc38a4, Sfmbt2, Slc22a3, Phlda2, Cdkn1c, and Dlk1) exhibited significant difference in gene expression between wild-type and IUGR. The majority of these imprinted candidates have been linked to IUGR in either mouse and/or human studies. Overall, imprinted genes as a whole are not more affected in IUGR samples than would be expected by chance based on the chi-square test. These results illustrate that though individual imprinted genes may be important regulator of IUGR, genes regulated by genomic imprinting as a whole are not more affected in this pregnancy complication.

Text

2011-03-29

Attribution-NonCommercial-NoDerivatives 4.0 International

http://hdl.handle.net/2429/33065

Genetics

University of British Columbia

UBCV

http://creativecommons.org/licenses/by-nc-nd/4.0/