It remains to be clarified whether DIO3 is a PEG, although mouse Dio3 is known to be preferentially but not exclusively expressed from a paternally derived chromosome. PEGs are shown in blue, MEGs in red, and the IG-DMR (CG4 and CG6) and the MEG3 -DMR (CG7) in green. Physical map of the 14q32.2 imprinted region and the deleted segments in patient 1 and her mother and in patient 2 (shaded in gray). Thus, the results provide a significant advance in the clarification of underlying epigenetic features that can act to regulate imprinting. To our knowledge, this is the first study demonstrating an essential function for the secondary DMR in the regulation of multiple imprinted genes. Importantly, in the body, the MEG3-DMR functions as an imprinting control center. Here, through analysis of patients with microdeletions recapitulating some or all of the uniparental disomy 14 phenotypes, we show that the IG-DMR acts as an upstream regulator for the methylation pattern of the MEG3-DMR in the body but not in the placenta.
Perturbed dosage of these imprinted genes, for example in patients with paternal and maternal uniparental disomy 14, causes distinct phenotypes. The human chromosome 14q32.2 imprinted region harbors the germline-derived primary DLK1-MEG3 intergenic differentially methylated region (IG-DMR) and the postfertilization-derived secondary MEG3-DMR, together with multiple imprinted genes. Imprinted genes are often located in clusters regulated by regions that are differentially methylated according to their parental origin. Genomic imprinting is a process causing genes to be expressed in a parent-of-origin specific manner-some imprinted genes are expressed from maternally inherited chromosomes and others from paternally inherited chromosomes.
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