Author Correction: Transcriptional responses of skeletal stem/progenitor cells to hindlimb unloading and recovery correlate with localized but not systemic multi-systems impacts

AbstractDisuse osteoporosis (DO) results from mechanical unloading of weight-bearing bones and causes structural changes that compromise skeletal integrity, leading to increased fracture risk. Although bone loss in DO results from imbalances in osteoblast vs. osteoclast activity, its effects on skeletal stem/progenitor cells (SSCs) is indeterminate. We modeled DO in mice by 8 and 14 weeks of hindlimb unloading (HU) or 8 weeks of unloading followed by 8 weeks of recovery (HUR) and monitored impacts on animal physiology and behavior, metabolism, marrow adipose tissue (MAT) volume, bone density and micro-architecture, and bone marrow (BM) leptin and tyrosine hydroxylase (TH) protein expression, and correlated multi-systems impacts of HU and HUR with the transcript profiles of Lin−LEPR+ SSCs and mesenchymal stem cells (MSCs) purified from BM. Using this integrative approach, we demonstrate that prolonged HU induces muscle atrophy, progressive bone loss, and MAT accumulation that paralleled increases in BM but not systemic leptin levels, which remained low in lipodystrophic HU mice. HU also induced SSC quiescence and downregulated bone anabolic and neurogenic pathways, which paralleled increases in BM TH expression, but had minimal impacts on MSCs, indicating a lack of HU memory in culture-expanded populations. Although most impacts of HU were reversed by HUR, trabecular micro-architecture remained compromised and time-resolved changes in the SSC transcriptome identified various signaling pathways implicated in bone formation that were unresponsive to HUR. These findings indicate that HU-induced alterations to the SSC transcriptome that persist after reloading may contribute to poor bone recovery.

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BF-1 Interferes with Transforming Growth Factor β Signaling by Associating with Smad Partners

Molecular and Cellular Biology ◽

10.1128/mcb.20.17.6201-6211.2000 ◽

2000 ◽

Vol 20 (17) ◽

pp. 6201-6211 ◽

Cited By ~ 65

Author(s):

Changlin Dou ◽

Jun Lee ◽

Bo Liu ◽

Fang Liu ◽

Joan Massague ◽

...

Keyword(s):

Growth Factor ◽

Dna Binding ◽

Growth Inhibition ◽

Progenitor Cells ◽

Transcriptional Activation ◽

Transforming Growth Factor ◽

Ectopic Expression ◽

Transforming Growth Factor Β ◽

Reporter System ◽

Transcriptional Responses

ABSTRACT The winged-helix (WH) BF-1 gene, which encodes brain factor 1 (BF-1) (also known as foxg1), is essential for the proliferation of the progenitor cells of the cerebral cortex. Here we show that BF-1-deficient telencephalic progenitor cells are more apt to leave the cell cycle in response to transforming growth factor β (TGF-β) and activin. We found that ectopic expression of BF-1 in vitro inhibits TGF-β mediated growth inhibition and transcriptional activation. Surprisingly, we found that the ability of BF-1 to function as a TGF-β antagonist does not require its DNA binding activity. Therefore, we investigated whether BF-1 can inhibit Smad-dependent transcriptional responses by interacting with Smads or Smad binding partners. We found that BF-1 does not interact with Smads. Because the identities of the Smad partners mediating growth inhibition by TGF-β are not clearly established, we examined a model reporter system which is known to be activated by activin and TGF-β through Smads and the WH factor FAST-2. We demonstrate that BF-1 associates with FAST-2. This interaction is dependent on the same region of protein which mediates its ability to interfere with the antiproliferative activity of TGF-β and with TGF-β-dependent transcriptional activation. Furthermore, the interaction of FAST-2 with BF-1 is mediated by the same domain which is required for FAST-2 to interact with Smad2. We propose a model in which BF-1 interferes with transcriptional responses to TGF-β by interacting with FAST-2 or with other DNA binding proteins which function as Smad2 partners and which have a common mode of interaction with Smad2.

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MON-727 The Chromatin Landscape of Glucocorticoid Regulated Genes in Mouse Embryonic Neural Stem / Progenitor Cells

Journal of the Endocrine Society ◽

10.1210/jendso/bvaa046.641 ◽

2020 ◽

Vol 4 (Supplement_1) ◽

Author(s):

Kimberly Berry ◽

Uma Chandran ◽

Fangping Mu ◽

Donald DeFranco

Keyword(s):

Progenitor Cells ◽

Target Genes ◽

Therapeutic Potential ◽

Transcriptional Response ◽

Clinical Intervention ◽

Enrichment Analysis ◽

Open Chromatin ◽

Transcriptional Responses ◽

Embryonic Mouse

Abstract Stem/Progenitor Cells Antenatal administration of Dexamethasone (Dex), a synthetic glucocorticoid (GC), is a common clinical intervention for women at risk for preterm birth or in preterm labor that effectively reduces fetal risk of mortality and bronchopulmonary-related comorbidities. Despite the therapeutic potential of Dex, excess GC act adversely in the developing central nervous system to reprogram distinct neural circuits in the brain by acting through the glucocorticoid receptor (GR). For example, prenatal exposure to excess GCs can impact neural stem and progenitor cell (NSPC) proliferation leading to long-term alterations in prefrontal cortical neuronal complexity, which could contribute to behavioral and cognitive impairments later in life. The GR is a member of the nuclear receptor superfamily that, when bound by a ligand, translocates from the cytoplasm to the nucleus and associates indirectly or directly with DNA elements (e.g. glucocorticoid responsive elements or GREs) resulting in the activation and/or repression of target genes. While GR-regulated transcriptomes have been identified in many NSPC models, the mechanisms responsible for programming these cells for GC-responsiveness remain largely unknown. We therefore used transposase accessible chromatin followed by genome-wide sequencing (Omni ATAC-seq) to characterize the chromatin landscape of primary embryonic mouse NSPCs in response to an acute in vitro treatment with Dex. We identified a small, yet distinct fraction (0.002%, p<0.05) of open chromatin sites that were Dex-inducible. 95% of these Dex-induced changes in chromatin accessibility occur within intronic or intergenic regions, suggesting the presence of long-range enhancer-promoter contacts that mediate NSPC transcriptional responses to Dex. Motif enrichment analysis revealed putative GRE sites located in Dex-inducible open chromatin within -5kb/+2kb of a Dex-induced gene, providing possible DNA targets of GR for further validation. A number of other transcription factors implicated in neurodevelopmental processes were found to underlie both Dex-inducible and constitutively open chromatin regions. Characterization of the precise epigenetic and transcriptional response to excess GC in-utero, and its influence on acute and chronic neurological outcomes, will encourage the development of alternative GC treatment regimens that could protect the developing brain from insult while providing optimal health outcomes in neonates.

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