Long non-coding RNA HoxA-AS3 interacts with EZH2 to regulate lineage commitment of mesenchymal stem cells

Abstract

Long non-coding RNAs (lncRNAs) play an important role in gene regulation and are involving in diverse cellular processes. However, their roles in reprogramming of gene expression profiles during lineage commitment and maturation of mesenchymal stem cells (MSCs) remain poorly understood. In the current study, we characterize the expression of a lncRNA, HoxA-AS3, during the differentiation of MSCs. We showed that HoxA-AS3 is increased upon adipogenic induction of MSCs, while HoxA-AS3 remains unaltered during osteogenic induction. Silencing of HoxA-AS3 in MSCs resulted in decreased adipogenesis and expression of adipogenic markers, PPARG, CEBPA, FABP4 and ADIPOQ. Conversely, knockdown of HoxA-AS3 expression in MSCs exhibited an enhanced osteogenesis and osteogenic markers expression, including RUNX2, SP7, COL1A1, IBSP, BGLAP and SPP1. Mechanistically, HoxA-AS3 interacts with Enhancer Of Zeste 2 (EZH2) and is required for H3 lysine-27 trimethylation (H3K27me3) of key osteogenic transcription factor Runx2. Our data reveal that HoxA-AS3 acts as an epigenetic switch that determines the lineage specification of MSC.

INO80 is Required for Osteogenic Differentiation of Human Mesenchymal Stem Cells

“…For example, involvement of histone acetylation in chondrogenic differentiation of MSCs has also been reported7. Intriguingly, a recent study showed that lncRNA HoxA-AS3 is required for adipogenesis of MSC8. HoxA-AS3 silencing in MSC lead to increase of osteogenic markers expression, including RUNX2, SP7, COL1A1, IBSP, BGLAP and SPP18.…”

“…HoxA-AS3 silencing in MSC lead to increase of osteogenic markers expression, including RUNX2, SP7, COL1A1, IBSP, BGLAP and SPP18. HoxA-AS3 functions together with EZH2 to modulate the status of H3K27me3 in the promoter region of key osteogenic transcription factor Runx28. This is an important study to provide evidence that MSC lineage commitment can be achieved through lncRNA regulation.…”

“…Intriguingly, a recent study showed that lncRNA HoxA-AS3 is required for adipogenesis of MSC8. HoxA-AS3 silencing in MSC lead to increase of osteogenic markers expression, including RUNX2, SP7, COL1A1, IBSP, BGLAP and SPP18. HoxA-AS3 functions together with EZH2 to modulate the status of H3K27me3 in the promoter region of key osteogenic transcription factor Runx28.…”

“…Furthermore, long non-coding RNAs (lncRNA) are also essential in regulating MSC lineage differentiation. Recent study has demonstrated that HoxA-AS3 can be associated with EZH2 and direct the lineage specification of MSC8, implying multiple epigenetic mechanism are involved in regulation of MSC differentiation.…”

SEMA3B‐AS1‐inhibited osteogenic differentiation of human mesenchymal stem cells revealed by quantitative proteomics analysis

“…Several studies have reported that lncRNAs, such as H19, lncRNA‐POIR, HOTAIR, and MEG3, alter miRNA biogenesis or function directly or indirectly (Huang et al, ; Li et al, ; Liang et al, ; Wang et al, ; Wei et al, ). HoxA‐AS3, on the other hand, directly modulates H3K27me3 activity on the key osteogenic transcription factor Runx2 to control the osteogenic lineage commitment (Zhu et al, ). As shown by both COG function classification and pathway enrichment analysis, proteins involved in “translation, ribosomal structure, and biogenesis” are ranked as top‐enriched candidates by iTRAQ analysis, which are also upregulated by SEMA3B‐AS1 as a “spliceosome” functional cluster, suggesting that epigenetic regulation of the osteogenic pathway can also be caused by SEMA3B‐AS1.…”