LncRNA NEAT1 controls the lineage fates of BMSCs during skeletal aging by impairing mitochondrial function and pluripotency maintenance

Abstract

Aged bone marrow mesenchymal stem cells (BMSCs) exhibit aberrant self-renewal and lineage specification, which contribute to imbalanced bone-fat and progressive bone loss. In addition to known master regulators of lineage commitment, it is crucial to identify pivotal switches governing the specific differentiation fate of aged BMSCs. Here, we profiled differences in epigenetic regulation between adipogenesis and osteogenesis and identified super-enhancer associated lncRNA nuclear-enriched abundant transcript 1 (NEAT1) as a key bone-fat switch in aged BMSCs. We validated that NEAT1 with high enhancer activity was transcriptionally activated by ATF2 and directed aged BMSCs to a greater propensity to differentiate toward adipocytes than osteoblasts by mediating mitochondrial function. Furthermore, we confirmed NEAT1 as a protein-binding scaffold in which phosphorylation modification of SOX2 Ser249/250 by CDK2 impaired SOX2/OCT4 complex stability and dysregulated downstream transcription networks of pluripotency maintenance. In addition, by sponging miR-27b-3p, NEAT1 upregulated BNIP3L, BMP2K, and PPARG expression to shape mitochondrial function and osteogenic/adipogenic differentiation commitment, respectively. In extracellular communication, NEAT1 promoted CSF1 secretion from aged BMSCs and then strengthened osteoclastic differentiation by extracellular vesicle delivery. Notably, Neat1 small interfering RNA delivery induced increased bone mass in aged mice and decreased fat accumulation in the bone marrow. These findings suggest that NEAT1 regulates the lineage fates of BMSCs by orchestrating mitochondrial function and pluripotency maintenance, and might be a potential therapeutic target for skeletal aging.

Breaking the aging epigenetic barrier

“…Nuclear-abundant lncRNAs NEAT1 and MALAT1 are shown to localize to hundreds of genomic sites in human cells, preferentially to active genes ( West et al, 2014 ). NEAT1 regulates aberrant self-renewal of bone marrow mesenchymal stem cell lineage during skeletal aging by mediating mitochondrial function ( Zhang et al, 2022 ). Whereas, in vascular endothelial cells SIRT6-mediated suppression of MALAT1 resulted in aging-induced endothelial to mesenchymal transition through Snail upregulation ( Qin et al, 2019 ).…”

Identification and Validation of CDKN1A and HDAC1 as Senescence-Related Hub Genes in Chronic Obstructive Pulmonary Disease

“…A previous study has implied that NEAT1 is upregulated in aged bone marrow mesenchymal stem cells (BMSCs) and regulates mitochondrial function by sponging miR-27b-3p. 41 Additionally, NEAT1 is a marker of COPD susceptibility, and NEAT1/miR-193a affects the development of COPD. 42 In CSE-exposed 16HBE cells, XIST/miR-200c-3p/EGR3 can intensify inflammation action and apoptosis.…”

CircRNA Profiling Reveals CircPPARγ Modulates Adipogenic Differentiation via Sponging miR-92a-3p

“…In addition, adipogenesis and adipose deposition are regulated by post-transcriptional factors, such as noncoding RNAs (ncRNAs) . Zhang et al identified transcriptional and epigenetic regulatory differences between adipogenesis and osteogenesis and identified NEAT1, a long ncRNA (lncRNA) associated with super-enhancers (SEs), as a key molecule in the differentiation of bone marrow stromal cells . Several studies have identified several ncRNAs that affect adipogenesis and adipose deposition during the various regulatory stages of adipocyte proliferation and differentiation. , …”

“…8 Zhang et al identified transcriptional and epigenetic regulatory differences between adipogenesis and osteogenesis and identified NEAT1, a long ncRNA (lncRNA) associated with super-enhancers (SEs), as a key molecule in the differentiation of bone marrow stromal cells. 9 Several studies have identified several ncRNAs that affect adipogenesis and adipose deposition during the various regulatory stages of adipocyte proliferation and differentiation. 10,11 Circular RNAs (circRNAs) are among the most valuable and important ncRNAs, referring to RNA molecules with a circular structure covalently linked at the 3′ and 5′ ends, constituting a recently discovered, widespread and abundant class of RNAs.…”