Histone Chaperone SSRP1 is Essential for Wnt Signaling Pathway Activity During Osteoblast Differentiation

Abstract

Cellular differentiation is accompanied by dramatic changes in chromatin structure which direct the activation of lineage-specific transcriptional programs. Structure-specific recognition protein-1 (SSRP1) is a histone chaperone which is important for chromatin-associated processes such as transcription, DNA replication and repair. Since the function of SSRP1 during cell differentiation remains unclear, we investigated its potential role in controlling lineage determination. Depletion of SSRP1 in human mesenchymal stem cells elicited lineage-specific effects by increasing expression of adipocyte-specific genes and decreasing the expression of osteoblast-specific genes. Consistent with a role in controlling lineage specification, transcriptome-wide RNA-sequencing following SSRP1 depletion and the induction of osteoblast differentiation revealed a specific decrease in the expression of genes involved in biological processes related to osteoblast differentiation. Importantly, we observed a specific downregulation of target genes of the canonical Wnt signaling pathway, which was accompanied by decreased nuclear localization of active b-catenin. Together our data uncover a previously unknown role for SSRP1 in promoting the activation of the Wnt signaling pathway activity during cellular differentiation. STEM CELLS 2016;34:1369-1376 SIGNIFICANCE STATEMENTEpigenetic regulation plays an essential role in defining lineage-specific gene expression patterns. We investigated the function of the histone chaperone SSRP1 during cellular differentiation and demonstrate its essential function in specifically directing multipotent mesenchymal stem cell differentiation to the osteoblast lineage via regulation of Wnt signaling. We thereby provide the first evidence of a lineage-specific role of SSRP1 during cellular differentiation and uncover molecular insights into its function, which may serve as a basis for future clinical application of small molecule modulators of its activity for the treatment of aging-related osteoporosis and other diseases associated with altered Wnt signaling.

SSRP1 promotes colorectal cancer progression and is negatively regulated by miR‐28‐5p

“…38 Furthermore, it has been reported that SSRP1 is involved in canonical Wnt/β-catenin-mediated signalling pathways. 11 The activation of the Wnt/β-catenin signalling pathway also plays a key role in the formation of CRC; mutations in the negative regulatory components of APC occur in more than 90% of colorectal tumours. 39 We have been suggested that the high expression levels of SSRP1 regulate the Wnt/β-catenin pathways in CRC.…”

“…10 SSRP1 is highly expressed in the early stages of embryonic development, and its expression is reduced gradually in the organs as birth nears and postnatal life begins, which suggests that SSRP1 plays a role in maintaining the undifferentiated cell state. [10][11][12] Moreover, SSRP1 is upregulated in various tumours, such as breast cancer and ovarian cancer, and is associated with a worse prognosis. [13][14][15] RNA interference (RNAi) knocks down SSRP1, inhibits tumour transformation and impairs tumour cell viability, but nontumour cells can tolerate this knockdown well.…”

Level of FACT defines the transcriptional landscape and aggressive phenotype of breast cancer cells

“…This was confirmed by in vitro induced differentiation experiments [22]. Several studies from other labs also showed that FACT is involved in the early steps of differentiation [23, 24], suggesting a role in actively proliferating progenitors of differentiated cells, the most probable source of cancer stem cells. Based on these findings, FACT elevation in multiple tumors, including BrCa [25] and ovarian cancer [26] was less surprising and more biologically explicable, though the mechanism by which FACT facilitates tumor growth is still obscure.…”

Krüppel-like Transcription Factor KLF10 Suppresses TGFβ-Induced Epithelial-to-Mesenchymal Transition via a Negative Feedback Mechanism

“…For luciferase assays, the Dual-Luciferase Reporter Assay System (Promega) was used as previously described (29). Briefly, cells were co-transfected with a SNAI2 -promoter containing luciferase promoter construct (kindly provided by S. Hüttelmaier; (30) together with a plasmid expressing Renilla luciferase (pRL-TK, Promega) and either an empty control vector (pSG5) or KLF10 expression vector.…”