Abstract
Most human genes are associated with promoters embedded in non-methylated, G + C-rich CpG islands (CGIs). Not all CGIs are found at annotated promoters, however, raising the possibility that many serve as promoters for transcripts that do not code for proteins. To test this hypothesis, we searched for novel transcripts in embryonic stem cells (ESCs) that originate within orphan CGIs. Among several candidates, we detected a transcript that included three members of the let-7 micro-RNA family: Let-7a-1, let-7f-1, and let-7d. Deletion of the CGI prevented expression of the precursor RNA and depleted the included miRNAs. Mice homozygous for this mutation were sub-viable and showed growth and other defects. The results suggest that despite the identity of their seed sequences, members of the let-7 miRNA family exert distinct functions that cannot be complemented by other members.
Highlights
CpG islands (CGIs) are domains of approximately 1000 base pairs that include the promoters of most mammalian genes [1]
E14Tg2a embryonic stem cells prior to differentiation; embryoid bodies (EBs) representing an intermediate stage of differentiation; and derivatives that had been further differentiated into neuronal cells
We identified a long transcript, which appeared to originate from CGI-5563 located on chromosome 13 (Figure 1A), which was recently annotated as KY467470
Summary
CpG islands (CGIs) are domains of approximately 1000 base pairs that include the promoters of most mammalian genes [1]. We investigated a transcript that serves as a precursor for let-7 micro-RNAs. Members of the let-7 family of (let-7a/b/c/d/e/f /g/i and miR-98) share a common seed sequence, nucleotides 2 through 8 of their 50 ends, which is required for target recognition [6]. Members of the let-7 family of (let-7a/b/c/d/e/f /g/i and miR-98) share a common seed sequence, nucleotides 2 through 8 of their 50 ends, which is required for target recognition [6] They were originally discovered in Caenorhabditis elegans, where they play crucial roles in the temporal regulation of development, with decreased expression resulting in over-proliferation and the absence of terminal differentiation.
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