Phosphoproteomic profiling reveals a defined genetic program for osteoblastic lineage commitment of human bone marrow–derived stromal stem cells

Barrio-Hernandez, Iñigo; Jafari, Abbas; Rigbolt, Kristoffer; Hallenborg, Philip; Sanchez-Quiles, Virginia; Skovrind, Ida; Akimov, Vyacheslav; Kratchmarova, Irina; Dengjel, Jörn; Kassem, Moustapha; Blagoev, Blagoy

doi:10.1101/gr.248286.119

Cited by 15 publications

(6 citation statements)

References 61 publications

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“…For transfected 293 T cells and unlabeled 3T3-L1 adipocytes, the precleared lysate was then incubated with anti-FLAG affinity gel (Sigma-Aldrich) for 6 h and rinsed four times in lysis buffer before SDS-PAGE. For the MDM2 and MORC2 interactome experiments, 3T3-L1 adipocytes were either double SILAC-labeled with Arg6/Lys4 and Arg10/Lys8, or triple SILAC-encoded with Arg0/Lys0, Arg6/Lys4, and Arg10/Lys8 65 , 66 , respectively. Precleared lysates from the SILAC-labeled adipocytes were then incubated with protein G beads coupled with nonspecific IgG or antibodies directed against MDM2 (4B2, SMP14 (sc-965, Santa Cruz), or 2A10 (OP115, Merck)) or MORC2 (SAB4301687, Merck) for 6 h, combined, rinsed four times in lysis buffer and separated on a NuPAGE gel (Invitrogen) and stained with Novex Colloidal Blue (Invitrogen, Thermo Fisher Scientific).…”

Section: Histologymentioning

confidence: 99%

Adipose MDM2 regulates systemic insulin sensitivity

Hallenborg

Jensen

Fjære

et al. 2021

Sci Rep

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The intimate association between obesity and type II diabetes urges for a deeper understanding of adipocyte function. We and others have previously delineated a role for the tumor suppressor p53 in adipocyte biology. Here, we show that mice haploinsufficient for MDM2, a key regulator of p53, in their adipose stores suffer from overt obesity, glucose intolerance, and hepatic steatosis. These mice had decreased levels of circulating palmitoleic acid [non-esterified fatty acid (NEFA) 16:1] concomitant with impaired visceral adipose tissue expression of Scd1 and Ffar4. A similar decrease in Scd and Ffar4 expression was found in in vitro differentiated adipocytes with perturbed MDM2 expression. Lowered MDM2 levels led to nuclear exclusion of the transcriptional cofactors, MORC2 and LIPIN1, and thereby possibly hampered adipocyte function by antagonizing LIPIN1-mediated PPARγ coactivation. Collectively, these data argue for a hitherto unknown interplay between MDM2 and MORC2/LIPIN1 involved in balancing adipocyte function.

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Section: Histologymentioning

confidence: 99%

Adipose MDM2 regulates systemic insulin sensitivity

Hallenborg

Jensen

Fjære

et al. 2021

Sci Rep

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“…This osteogenic function-promoting effect exists both in vitro and in vivo ( 123 ). Studies on several HDAC subtypes, including HDAC1, HDAC2, HDAC3, HDAC4, HDAC5, HDAC6, HDAC7, and HDAC8 ( 119 , 145 – 149 ), have confirmed these findings. In addition, reduced histone acetylation modifications triggered by other deacetylases have been reported to inhibit osteogenesis, such as the H3K9 deacetylase SIRT6, which regulates osteogenic differentiation of MSCs through the SIRT6-TRPV1-CGRP signaling axis ( 150 ).…”

Section: Epigenetic Control Of Mscs In Bone Regenerationmentioning

confidence: 65%

Epigenetic control of mesenchymal stem cells orchestrates bone regeneration

2023

Front. Endocrinol.

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Recent studies have revealed the vital role of MSCs in bone regeneration. In both self-healing bone regeneration processes and biomaterial-induced healing of bone defects beyond the critical size, MSCs show several functions, including osteogenic differentiation and thus providing seed cells. However, adverse factors such as drug intake and body senescence can significantly affect the functions of MSCs in bone regeneration. Currently, several modalities have been developed to regulate MSCs’ phenotype and promote the bone regeneration process. Epigenetic regulation has received much attention because of its heritable nature. Indeed, epigenetic regulation of MSCs is involved in the pathogenesis of a variety of disorders of bone metabolism. Moreover, studies using epigenetic regulation to treat diseases are also being reported. At the same time, the effects of epigenetic regulation on MSCs are yet to be fully understood. This review focuses on recent advances in the effects of epigenetic regulation on osteogenic differentiation, proliferation, and cellular senescence in MSCs. We intend to illustrate how epigenetic regulation of MSCs orchestrates the process of bone regeneration.

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“…As a result, inhibited expression of HDAC7 might lead to an enhancement in osteoclast formation possibly entailing increased bone resorption. In addition, HDAC7 represses RUNX2 mediated histone acetylation, thus, impacting osteoblastic lineage commitment [ 101 , 102 ].…”

Section: Discussionmentioning

confidence: 99%

The role of DNA methylation on gene expression in the vertebrae of ancestrally benzo[a]pyrene exposed F1 and F3 male medaka

Wan

et al. 2023

Epigenetics

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Benzo[a]pyrene (BaP) is ubiquitously present in the aquatic environment and has been identified as a bone toxicant. Previous studies have demonstrated that ancestral BaP exposure can cause transgenerational bone deformities in fish. Transgenerational effects are thought to be caused by heritable epigenetic changes, such as DNA methylation, histone modification, and non-coding RNAs. To investigate the role of DNA methylation in BaP-induced transgenerational skeletal deformities and the related transcriptomic changes in deformed vertebrae, we examined the vertebrae of male F1 and F3 medaka fish using high-throughput RNA sequencing (RNA-seq) and whole-genome bisulphite sequencing (WGBS). The histological results revealed that osteoblast numbers at the vertebral bone decreased in the BaP-derived F1 and F3 adult males in comparison with the control group. Differentially methylated genes (DMGs) associated with osteoblastogenesis (F1 and F3), chondrogenesis (F1 and F3), and osteoclastogenesis (F3) were identified. However, RNA-seq data did not support the role of DNA methylation in the regulation of genes involved in skeletogenesis since there was very little correlation between the level of differential methylation and gene expression profiles related to skeletogenesis. Although DNA methylation plays a major role in the epigenetic regulation of gene expression, the dysregulation of vertebral gene expression patterns observed in the current study is most likely to be mediated by histone modification and miRNAs. Notably, RNA-seq and WGBS data indicated that genes related to nervous system development are more sensitive to ancestral BaP exposure, indicating a more complex transgenerational phenotype in response to ancestral BaP exposure.

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Phosphoproteomic profiling reveals a defined genetic program for osteoblastic lineage commitment of human bone marrow–derived stromal stem cells

Cited by 15 publications

References 61 publications

Adipose MDM2 regulates systemic insulin sensitivity

Adipose MDM2 regulates systemic insulin sensitivity

Epigenetic control of mesenchymal stem cells orchestrates bone regeneration

The role of DNA methylation on gene expression in the vertebrae of ancestrally benzo[a]pyrene exposed F1 and F3 male medaka

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