Domain-specific response of imprinted genes to reduced DNMT1.
Imprinted genes are expressed in a monoallelic, parent-of-origin-specific manner. Clusters of imprinted genes are regulated by imprinting control regions (ICRs) characterized by DNA methylation of one allele. This methylation is critical for imprinting; a reduction in the DNA methyltransferase DNMT1 causes a widespread loss of imprinting. To better understand the role of DNA methylation in the regulation of imprinting, we characterized the effects of Dnmt1 mutations on the expression of a panel of imprinted genes in the embryo and placenta. We found striking differences among imprinted domains. The Igf2 and Peg3 domains showed imprinting perturbations with both null and partial loss-of-function mutations, and both domains had pairs of coordinately regulated genes with opposite responses to loss of DNMT1 function, suggesting these domains employ similar regulatory mechanisms. Genes in the Kcnq1 domain were less sensitive to the absence of DNMT1. Cdkn1c exhibited imprinting perturbations only in null mutants, while Kcnq1 and Ascl2 were largely unaffected by a loss of DNMT1 function. These results emphasize the critical role for DNA methylation in imprinting and reveal the different ways it controls gene expression.
Weaver
Jamie R
JR
Department of Cell and Developmental Biology, University of Pennsylvania School of Medicine, CRB 363, Philadelphia, PA 19104, USA.
Sarkisian
Garnik
G
Krapp
Christopher
C
Mager
Jesse
J
Mann
Mellissa R W
MR
Bartolomei
Marisa S
MS
D000483:Alleles; D000818:Animals; D001483:Base Sequence; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics; D003433:Crosses, Genetic; D000076123:DNA (Cytosine-5-)-Methyltransferase 1; D004248:DNA (Cytosine-5-)-Methyltransferases / Q000737:chemistry / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism; D019175:DNA Methylation; D017931:DNA Primers / Q000235:genetics; D005260:Female; D018507:Gene Expression Regulation, Developmental; D018392:Genomic Imprinting; D007335:Insulin-Like Growth Factor II / Q000235:genetics; D051657:KCNQ1 Potassium Channel / Q000235:genetics; D051741:Kruppel-Like Transcription Factors / Q000235:genetics; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D005810:Multigene Family; D050505:Mutant Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D010920:Placenta / Q000378:metabolism; D011247:Pregnancy; D017434:Protein Structure, Tertiary
D051792:Basic Helix-Loop-Helix Proteins; D000076123:DNA (Cytosine-5-)-Methyltransferase 1; D004248:DNA (Cytosine-5-)-Methyltransferases; D017931:DNA Primers; D007335:Insulin-Like Growth Factor II; D051657:KCNQ1 Potassium Channel; D051741:Kruppel-Like Transcription Factors; D050505:Mutant Proteins; C489311:Ascl2 protein, mouse; C513121:IGF2 protein, mouse; C496910:Kcnq1 protein, mouse; C097901:Peg3 protein, mouse; C000619381:Dnmt1 protein, mouse