Comprehensive MicroRNA Profiling Reveals a Unique Human Embryonic Stem Cell Signature Dominated by a Single Seed Sequence

Abstract

Embryonic stem cells are unique among cultured cells in their ability to self-renew and differentiate into a wide diversity of cell types, suggesting that a specific molecular control network underlies these features. Human embryonic stem cells (hESCs) are known to have distinct mRNA expression, global DNA methylation, and chromatin profiles, but the involvement of high-level regulators, such as microRNAs (miRNA), in the hESC-specific molecular network is poorly understood. We report that global miRNA expression profiling of hESCs and a variety of stem cell and differentiated cell types using a novel microarray platform revealed a unique set of miRNAs differentially regulated in hESCs, including numerous miRNAs not previously linked to hESCs. These hESC-associated miRNAs were more likely to be located in large genomic clusters, and less likely to be located in introns of coding genes. hESCs had higher expression of oncogenic miRNAs and lower expression of tumor suppressor miRNAs than the other cell types. Many miRNAs upregulated in hESCs share a common consensus seed sequence, suggesting that there is cooperative regulation of a critical set of target miRNAs. We propose that miRNAs are coordinately controlled in hESCs, and are key regulators of pluripotence and differentiation. STEM CELLS

Determination of the Human Cardiomyocyte mRNA and miRNA Differentiation Network by Fine-Scale Profiling

“…The pluripotency-associated miR-302 cluster (miR-302a, -302b, -302c, -302d, and -367) declined over the differentiation time course (Fig. 3B), as expected [39,40]. Although the levels of the miRNAs never returned to baseline, even at 120 days, such residual miR-302 expression has been observed in other differentiation experiments [39,41,42].…”

“…3B), as expected [39,40]. Although the levels of the miRNAs never returned to baseline, even at 120 days, such residual miR-302 expression has been observed in other differentiation experiments [39,41,42]. The let-7 family of miRNAs, which reinforce the commitment to differentiation [43], also exhibited the expected expression pattern with the levels increasing during differentiation (Supplementary Fig.…”

Analysis of microRNAs in a knock-in hESC line expressing epitope-tagged AGO2

“…The miRNA profile showed the hESC-specific expression signature (Figure 2(b)), consistent with previous studies (Suh et al 2004;Laurent et al 2008). First, miRNAs bearing the ESC-specific seed (AAGUGCU), which originated predominantly from the miR-302-367 cluster and to a much lesser degree, from the miR-371-373 cluster, were dominant.…”

Reactivation of epigenetically silenced miR-512 and miR-373 sensitizes lung cancer cells to cisplatin and restricts tumor growth

“…We found that inhibition of epigenetic silencing caused upregulation of two miR clusters located on chromosome 19: the C19MC (ch19 miR cluster) and the miR-371-373 cluster, both associated with human embryonic stem cells. 14 We subsequently focused on one representative miR from each cluster: miR-512-5p (miR-512) and miR-373, respectively. We report that both miRs can exert negative effects on lung cancer cells, including induction of apoptosis and inhibition of cell migration.…”