Lineage-selective super enhancers mediate core regulatory circuitry during adipogenic and osteogenic differentiation of human mesenchymal stem cells

Wang, Chen; Tian, Wen; Hu, Shou-Ye; Di, Chen-Xi; He, Changyi; Cao, Qilong; Hao, Ruo-Han; Dong, Shanshan; Liu, Congcong; Yu, Rong; Kang, Huafeng; Yang, Tie-Lin; Yang, Zhi; Guo, Yan

doi:10.1038/s41419-022-05309-3

Cited by 5 publications

(7 citation statements)

References 64 publications

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“…This suggests that the osteogenic differentiation in vitro recapitulates to some extent what osteogenesis occurs in vivo . As differentiation progressed, we observed an upregulation in Runx2 67 , Runx1 68 , Glis3 69 , and Mef2a 70,71 , which reported to play pivotal roles in transitioning osteoprogenitor cells to mature osteoblasts. In adipogenesis, the roles of CEBP and PPAR as adipogenic inducers are well-established 72 .…”

Section: Discussionmentioning

confidence: 75%

The Hippo-YAP/TAZ-TEAD axis promotes multipotency in bone marrow stromal cells

Cheng,

Chan,

Bian

et al. 2024

Preprint

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The mechanisms by which bone marrow stromal cells (BMSCs) maintain multilineage potency in vitro remain elusive. To identify the transcriptional regulatory circuits that contribute to BMSC multipotency, we performed paired single-nucleus multiomics of the expansion of freshly isolated BMSCs and of BMSCs undergoing tri-lineage differentiation. By computationally reconstructing the regulatory programs associated with initial stages of differentiation and early expansion, we identified the TEAD family of transcription factors, which is inhibited by Hippo signaling, as highly active in the BMSC in vitro multipotent state. Pharmacological inhibition of TEAD enhanced BMSC osteogenic and adipogenic differentiation, whereas its activation maintained BMSCs in an undifferentiated state, supporting a model whereby isolation of BMSCs coincides with a TEAD-controlled transcriptional state linked to multipotency. Our study highlights the Hippo pathway as a pivotal regulator of BMSC multipotency, and our regulatory network inferences are a reservoir of testable hypotheses that link transcription factors and their regulons to specific aspects of BMSC behavior.

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Section: Discussionmentioning

confidence: 75%

The Hippo-YAP/TAZ-TEAD axis promotes multipotency in bone marrow stromal cells

Cheng,

Chan,

Bian

et al. 2024

Preprint

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“…BM-MSCs are pluripotent stem cells with self-renewal and multidirectional differentiation abilities that are the precursor cells of osteoblasts and adipocytes ( 35 ). There is a mutual balance and modulation between these two differentiation trends ( 36 ).…”

Section: Balance Of Osteogenesis and Adipogenesismentioning

confidence: 99%

Obesity and lipid metabolism in the development of osteoporosis (Review)

Wang,

Zhang,

Zhao

et al. 2024

Int J Mol Med

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Osteoporosis is a common bone metabolic disease that causes a heavy social burden and seriously threatens life. Improving osteogenic capacity is necessary to correct bone mass loss in the treatment of osteoporosis. Osteoblasts are derived from the differentiation of bone marrow mesenchymal stem cells, a process that opposes adipogenic differentiation. The peroxisome proliferator-activated receptor γ and Wnt/β-catenin signaling pathways mediate the mutual regulation of osteogenesis and adipogenesis. Lipid substances play an important role in the occurrence and development of osteoporosis. The content and proportion of lipids modulate the activity of immunocytes, mainly macrophages, and the secretion of inflammatory factors, such as IL-1, IL-6 and TNF-α. These inflammatory effectors increase the activity and promote the differentiation of osteoclasts, which leads to bone imbalance and stronger bone resorption. Obesity also decreases the activity of antioxidases and leads to oxidative stress, thereby inhibiting osteogenesis. The present review starts by examining the bidirectional differentiation of BM-MScs, describes in detail the mechanism by which lipids affect bone metabolism, and discusses the regulatory role of inflammation and oxidative stress in this process. The review concludes that a reasonable adjustment of the content and proportion of lipids, and the alleviation of inflammatory storms and oxidative damage induced by lipid imbalances, will improve bone mass and treat osteoporosis. Contents1. Introduction 2. Obesity-induced osteoporosis 3. Balance of osteogenesis and adipogenesis 4. Hyperlipemia-induced pathological changes and osteoporosis 5. Lipids and osteoporosis 6. Obesity in postmenopausal osteoporosis 7. Lipid metabolism disorders in osteoporotic patients with diabetes 8. discussion

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“…The copyright holder for this preprint this version posted June 12, 2024. ; https://doi.org/10.1101/2024.06.11.598401 doi: bioRxiv preprint described before 38 . Peaks presented only in one sample were removed and the others were merged to produce a consistent peak set.…”

Section: Atac-seq Datamentioning

confidence: 99%

“…We and others had revealed the impacts of genetic variants on disrupting the TF binding on DNA and the consequent gene expression alteration [37][38][39][40][41][42] . As shown in Fig.…”

Section: Tf Binding-disruption (Tbd) Evariantsmentioning

confidence: 99%

Comprehensive profiling of transcriptional regulation in cartilage reveals pathogenesis of osteoarthritis

Tian,

Dong,

Jiang

et al. 2024

Preprint

Self Cite

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Cartilage damage is a leading cause of osteoarthritis (OA) etiology, however, the underlying mechanism governing gene expression regulation in this progress is poorly understood. Here, we described a comprehensive profiling of transcriptional regulation of 234 primary human cartilage samples. Based on speculated chondrocyte subtype proportions, we demonstrated the heterogeneity of cell composition contributed to the variance of gene expression across samples. We identified 3,232 significant expression quantitative trait loci (eQTLs) for 2,999 genes. Cell type-interaction eQTL (ci-eQTL) analyses revealed the regulation relationship of 81 eQTL-gene pairs showing cell type dependency. Further, by integrating with genome-wide association studies (GWASs) data of OA, we nominated 55 candidate effector genes, of which, 26 were novel genes that have not been reported by previous studies. Finally, we established a multi-level functional variants-deciphering pipeline by integrating the cartilage-specific ATAC-seq data, and identified 112 causal eQTLs that display allele-specific open chromatin (ASoC), as well as 410 transcription factor binding-disruption (TBD) eQTLs. We experimentally verified that the T allele at rs11750646, which was located within a GWAS-eQTL co-localized region, increased the AR binding affinity to an open chromatin region and promoted the expression of an OA-related genePIK3R1. Altogether, our findings provide new insights into the unique regulatory landscape of cartilage and elucidate potential mechanisms underlying the OA pathogenesis.

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Lineage-selective super enhancers mediate core regulatory circuitry during adipogenic and osteogenic differentiation of human mesenchymal stem cells

Cited by 5 publications

References 64 publications

The Hippo-YAP/TAZ-TEAD axis promotes multipotency in bone marrow stromal cells

The Hippo-YAP/TAZ-TEAD axis promotes multipotency in bone marrow stromal cells

Obesity and lipid metabolism in the development of osteoporosis (Review)

Comprehensive profiling of transcriptional regulation in cartilage reveals pathogenesis of osteoarthritis

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