Gene regulation is a complex process that orchestrates the precise timing and location of both gene activation and gene silencing. Genomic imprinting is a specialized mechanism whereby a gene displays silencing of one parental allele. The imprinted region on human chromosome 11p15.5 and its homologous domain in the mouse consists of a cluster of genes that are silenced on the paternal chromosome by an antisense non-coding RNA, Kcnq1ot1. Very little is known of the molecular mechanisms involved in allele-specific silencing and the role of the non-coding RNAs in modulating this process. This proposal will first exploit transgenic RNA interference technology to test the role of Kcnq1ot1 in establishing imprinting at this locus. In the second and third aims, we will study the epigenetic processes that allow some genes to escape silencing, applying a combination of bioinformatic, biochemical and in vivo approaches to identify regulatory elements in this domain that interact physically and create transcriptionally active domains interspersed with the silenced regions. Identifying the molecular mechanisms underlying the establishment and maintenance of imprinting will advance our understanding of human growth defects and disease.
Genes in the imprinted Kcnq1 domain are involved in Beckwith-Wiedemann syndrome, which causes prenatal overgrowth and predisposition to cancer. Loss of imprinting has been implicated in several human neoplasias. This proposal will provide a more thorough understanding of the regulatory mechanisms deployed in allele-specific gene silencing and will give insight into how these mechanisms can go awry in human disease.
|Werner, Rachael J; Schultz, Bryant M; Huhn, Jacklyn M et al. (2017) Sex chromosomes drive gene expression and regulatory dimorphisms in mouse embryonic stem cells. Biol Sex Differ 8:28|
|Romasko, Edward J; Engel, Nora (2016) Male-Specific Transcription Factor Occupancy Alone Does Not Account for Differential Methylation at Imprinted Genes in the mouse Germ Cell Lineage. G3 (Bethesda) 6:3975-3983|
|Schultz, Bryant M; Gallicio, Gwendolyn A; Cesaroni, Matteo et al. (2015) Enhancers compete with a long non-coding RNA for regulation of the Kcnq1 domain. Nucleic Acids Res 43:745-59|
|Barrio-Real, Laura; Benedetti, Lorena G; Engel, Nora et al. (2014) Subtype-specific overexpression of the Rac-GEF P-REX1 in breast cancer is associated with promoter hypomethylation. Breast Cancer Res 16:441|
|de la Casa Esperón, Elena; Cordier, Gaëlle; Engel, Nora (2012) A genomic reservoir for Tnfrsf genes is developmentally regulated and imprinted in the mouse. Epigenetics 7:626-34|
|Latham, Keith E; Sapienza, Carmen; Engel, Nora (2012) The epigenetic lorax: gene-environment interactions in human health. Epigenomics 4:383-402|
|Korostowski, Lisa; Sedlak, Natalie; Engel, Nora (2012) The Kcnq1ot1 long non-coding RNA affects chromatin conformation and expression of Kcnq1, but does not regulate its imprinting in the developing heart. PLoS Genet 8:e1002956|
|Korostowski, Lisa; Raval, Anjali; Breuer, Gillian et al. (2011) Enhancer-driven chromatin interactions during development promote escape from silencing by a long non-coding RNA. Epigenetics Chromatin 4:21|