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Role of LINE-1 retrotransposons in the human disease DiGeorge Syndrome (L1-DIGEORGESYNDROME)
Start date: Jun 1, 2012, End date: Nov 21, 2016 PROJECT  FINISHED 

Long INterspersed Element 1 (LINE-1s or L1s) is a highly abundant retrotransposon comprising 17% of the human genome. Most L1s are retrotransposition defective, but there are approximately 100 full-length active L1s (RC-L1s) in an average human genome. The activity of RC-L1s impacts the human genome in a myriad of ways, and several human diseases have been caused by the activity of L1s.The Drosha-DGCR8 complex (microprocessor) has a well-characterized role in microRNA (miRNA) biogenesis. DGCR8 contains two double-stranded RNA binding motifs that recognize the RNA substrate, whereas Drosha functions as the endonuclease. The microprocessor complex process pri-miRNAs that are further processed by Dicer in the cytoplasm to generate the mature miRNAs, which participate in several biological processes.In work I conducted as a post-doctoral fellow, we demonstrated that the microprocessor complex regulate LINE-1. Briefly, we demonstrated that the microprocessor complex could process primary transcripts resembling the 5’UTR of RC-L1s. Using a cell based L1 retrotransposition assay, we also observed that the microprocessor complex negatively regulates L1 mobilization. Thus, these results suggest that the microprocessor complex may act to regulate L1 retrotransposition, as a defender of human genome integrity.Notably, the human disease DiGeorge Syndrome (DGS) is characterized by the loss of the human gene DGRC8. Briefly, DGS affects between 1/2000 and 1/4000 live births, and most importantly it is one of the most common causes of mental retardation. The disease affects many parts of the human body (birth defects, learning disabilities, and recurrent infections).The Garcia-Perez lab has established that L1s are expressed and mobilized during early stages of human embryonic development. In the current Research Project, we aim to establish a human model of DGS using induced pluripotent stem cells, to determine the role of L1 in the pathogenesis DGS.

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