干旱区生态环境知识资源中心(Arid): BMP2-dependent gene regulatory network analysis reveals Klf4 as a novel transcription factor of osteoblast differentiation

Arid

DOI	10.1038/s41419-021-03480-7
	BMP2-dependent gene regulatory network analysis reveals Klf4 as a novel transcription factor of osteoblast differentiation
	Yu, Shuaitong; Guo, Jinqiang; Sun, Zheyi; Lin, Chujiao; Tao, Huangheng; Zhang, Qian; Cui, Yu; Zuo, Huanyan; Lin, Yuxiu; Chen, Shuo; Liu, Huan; Chen, Zhi
通讯作者	Liu, H ; Chen, Z (corresponding author), Wuhan Univ, Minist Educ KLOBM, Sch & Hosp Stomatol, State Key Lab Breeding Base Basic Sci Stomatol Hu, Wuhan, Peoples R China. ; Liu, H ; Chen, Z (corresponding author), Wuhan Univ, Minist Educ KLOBM, Sch & Hosp Stomatol, Key Lab Oral Biomed, Wuhan, Peoples R China. ; Liu, H (corresponding author), Wuhan Univ, Dept Periodontol, Sch & Hosp Stomatol, Wuhan, Peoples R China.
来源期刊	CELL DEATH & DISEASE
ISSN	2041-4889
出版年	2021
卷号	12 期号:2
英文摘要	Transcription factors (TFs) regulate the expression of target genes, inducing changes in cell morphology or activities needed for cell fate determination and differentiation. The BMP signaling pathway is widely regarded as one of the most important pathways in vertebrate skeletal biology, of which BMP2 is a potent inducer, governing the osteoblast differentiation of bone marrow stromal cells (BMSCs). However, the mechanism by which BMP2 initiates its downstream transcription factor cascade and determines the direction of differentiation remains largely unknown. In this study, we used RNA-seq, ATAC-seq, and animal models to characterize the BMP2-dependent gene regulatory network governing osteoblast lineage commitment. Sp7-Cre; Bmp2(fx/fx) mice (BMP2-cKO) were generated and exhibited decreased bone density and lower osteoblast number (n>6). In vitro experiments showed that BMP2-cKO mouse bone marrow stromal cells (mBMSCs) had an impact on osteoblast differentiation and deficient cell proliferation. Osteogenic medium induced mBMSCs from BMP2-cKO mice and control were subjected to RNA-seq and ATAC-seq analysis to reveal differentially expressed TFs, along with their target open chromatin regions. Combined with H3K27Ac CUT&Tag during osteoblast differentiation, we identified 2338 BMP2-dependent osteoblast-specific active enhancers. Motif enrichment assay revealed that over 80% of these elements were directly targeted by RUNX2, DLX5, MEF2C, OASIS, and KLF4. We deactivated Klf4 in the Sp7+lineage to validate the role of KLF4 in osteoblast differentiation of mBMSCs. Compared to the wild-type, Sp7-Cre; Klf4(fx/+) mice (KLF4-Het) were smaller in size and had abnormal incisors resembling BMP2-cKO mice. Additionally, KLF4-Het mice had fewer osteoblasts and decreased osteogenic ability. RNA-seq and ATAC-seq revealed that KLF4 mainly co-bound with RUNX2 to regulate downstream genes. Given the significant overlap between KLF4- and BMP2-dependent NFRs and enriched motifs, our findings outline a comprehensive BMP2-dependent gene regulatory network specifically governing osteoblast differentiation of the Sp7+lineage, in which Klf4 is a novel transcription factor.
类型	Article
语种	英语
开放获取类型	gold, Green Published
收录类别	SCI-E
WOS记录号	WOS:000621198700002
WOS类目	Cell Biology
WOS研究方向	Cell Biology
资源类型	期刊论文
条目标识符	http://119.78.100.177/qdio/handle/2XILL650/349819
作者单位	[Yu, Shuaitong; Guo, Jinqiang; Sun, Zheyi; Lin, Chujiao; Tao, Huangheng; Zhang, Qian; Cui, Yu; Zuo, Huanyan; Lin, Yuxiu; Liu, Huan; Chen, Zhi] Wuhan Univ, Minist Educ KLOBM, Sch & Hosp Stomatol, State Key Lab Breeding Base Basic Sci Stomatol Hu, Wuhan, Peoples R China; [Yu, Shuaitong; Guo, Jinqiang; Sun, Zheyi; Lin, Chujiao; Tao, Huangheng; Zhang, Qian; Cui, Yu; Zuo, Huanyan; Lin, Yuxiu; Liu, Huan; Chen, Zhi] Wuhan Univ, Minist Educ KLOBM, Sch & Hosp Stomatol, Key Lab Oral Biomed, Wuhan, Peoples R China; [Chen, Shuo] Univ Texas Hlth Sci Ctr San Antonio, Dept Dev Dent, San Antonio, TX 78229 USA; [Liu, Huan] Wuhan Univ, Dept Periodontol, Sch & Hosp Stomatol, Wuhan, Peoples R China
推荐引用方式 GB/T 7714	Yu, Shuaitong,Guo, Jinqiang,Sun, Zheyi,et al. BMP2-dependent gene regulatory network analysis reveals Klf4 as a novel transcription factor of osteoblast differentiation[J],2021,12(2).
APA	Yu, Shuaitong.,Guo, Jinqiang.,Sun, Zheyi.,Lin, Chujiao.,Tao, Huangheng.,...&Chen, Zhi.(2021).BMP2-dependent gene regulatory network analysis reveals Klf4 as a novel transcription factor of osteoblast differentiation.CELL DEATH & DISEASE,12(2).
MLA	Yu, Shuaitong,et al."BMP2-dependent gene regulatory network analysis reveals Klf4 as a novel transcription factor of osteoblast differentiation".CELL DEATH & DISEASE 12.2(2021).