Human long non-coding RNAs promote pluripotency and neuronal differentiation by association with chromatin modifiers and transcription factors

Abstract

Long non-coding RNAs (lncRNAs) are a numerous class of newly discovered genes in the human genome, which have been proposed to be key regulators of biological processes, including stem cell pluripotency and neurogenesis. However, at present very little functional characterization of lncRNAs in human differentiation has been carried out. In the present study, we address this using human embryonic stem cells (hESCs) as a paradigm for pluripotency and neuronal differentiation. With a newly developed method, hESCs were robustly and efficiently differentiated into neurons, and we profiled the expression of thousands of lncRNAs using a custom-designed microarray. Some hESC-specific lncRNAs involved in pluripotency maintenance were identified, and shown to physically interact with SOX2, and PRC2 complex component, SUZ12. Using a similar approach, we identified lncRNAs required for neurogenesis. Knockdown studies indicated that loss of any of these lncRNAs blocked neurogenesis, and immunoprecipitation studies revealed physical association with REST and SUZ12. This study indicates that lncRNAs are important regulators of pluripotency and neurogenesis, and represents important evidence for an indispensable role of lncRNAs in human brain development.

Two Novel Splice Variants of SOX2OT, SOX2OT-S1, and SOX2OT-S2 are Coupregulated with SOX2 and OCT4 in Esophageal Squamous Cell Carcinoma

“…However, little is known about their functional involvement in human neural differentiation [37,42]. We also examined the expression patterns of SOX2OT and its two novel variants during the course of neural differentiation of NT2 cells.…”

“…Accordingly, expression patterns of several lncRNAs correlate with those of pluripotency regulators such as OCT4, Nanog, and SOX2 [37,38]. SOX2 is an intronless gene that lies within the third intron of another gene known as SOX2OT [28].…”

Identification of linc-NeD125, a novel long non coding RNA that hosts miR-125b-1 and negatively controls proliferation of human neuroblastoma cells

“…29 We found that this transcript was almost undetectable both in undifferentiated and in RA-treated BE(2)-C cells (Fig. 2SC).…”

Epigenetic setting and reprogramming for neural cell fate determination and differentiation

“…Ng et al [41] screened the expression of lncRNAs before and after induction of human ESC differentiation into dopaminergic neurons and found that lncRNA_N1, _N2 and _N3 were weakly but significantly expressed after induction of neuronal differentiation. lncRNA_N1 and lncRNA_N3 might function as scaffolds for the interaction with transcription repressors, repressor element 1 (RE1; also called NRSE) silencing TF (REST; also called NRSF) and a PRC2 protein, suppressor of zeste 12 homologue (SUZ12), respectively, resulting in inhibition of their suppressor activity [41].…”

“…lncRNA_N1 and lncRNA_N3 might function as scaffolds for the interaction with transcription repressors, repressor element 1 (RE1; also called NRSE) silencing TF (REST; also called NRSF) and a PRC2 protein, suppressor of zeste 12 homologue (SUZ12), respectively, resulting in inhibition of their suppressor activity [41]. On the other hand, small modulatory dsRNAs encoding the RE1 sequence were found in the nucleus, where they interacted with the REST complex to promote transcription of RE1-associated genes [42].…”