Runx2 regulates chromatin accessibility to direct the osteoblast program at neonatal stages

被引：37

作者：

Hojo, Hironori ^{[1
,2
]}

Saito, Taku ^{[3
]}

He, Xinjun ^{[4
]}

Guo, Qiuyu ^{[4
]}

Onodera, Shoko ^{[5
]}

Azuma, Toshifumi ^{[5
]}

Koebis, Michinori ^{[6
]}

Nakao, Kazuki ^{[6
]}

Aiba, Atsu ^{[6
]}

Seki, Masahide ^{[7
]}

Suzuki, Yutaka ^{[7
]}

Okada, Hiroyuki ^{[1
,3
]}

Tanaka, Sakae ^{[3
]}

Chung, Ung-il ^{[1
,2
]}

McMahon, Andrew P. ^{[4
]}

Ohba, Shinsuke ^{[1
,8
,9
]}

机构：

[1] Univ Tokyo, Grad Sch Med, Ctr Dis Biol & Integrat Med, Lab Clin Biotechnol, Tokyo 1138655, Japan

[2] Univ Tokyo, Grad Sch Engn, Dept Bioengn, Tokyo 1138655, Japan

[3] Univ Tokyo, Grad Sch Med, Orthoped Surg, Tokyo 1138655, Japan

[4] Univ Southern Calif, Eli & Edythe Broad CIRM Ctr Regenerat Med & Stem, Dept Stem Cell Biol & Regenerat Med, Los Angeles, CA 90033 USA

[5] Tokyo Dent Coll, Dept Biochem, Tokyo 1010061, Japan

[6] Univ Tokyo, Grad Sch Med, Ctr Dis Biol & Integrat Med, Lab Anim Resources, Tokyo 1130033, Japan

[7] Univ Tokyo, Grad Sch Frontier Sci, Dept Computat Biol & Med Sci, Chiba 2778562, Japan

[8] Nagasaki Univ, Inst Biomed Sci, Dept Cell Biol, Nagasaki 8528588, Japan

[9] Osaka Univ, Grad Sch Dent, Dept Oral Anat & Dev Biol, Osaka 5650871, Japan

来源：

CELL REPORTS | 2022年 / 40卷 / 10期

基金：

日本科学技术振兴机构; 美国国家卫生研究院;

关键词：

HYPERTROPHIC CHONDROCYTE DIFFERENTIATION; FAMILY-MEMBERS; BETA INTERACTS; BONE-FORMATION; GENE; EXPRESSION; CBFA1; BINDING; LINEAGE; LANDSCAPE;

D O I：

10.1016/j.celrep.2022.111315

中图分类号：

Q2 [细胞生物学];

学科分类号：

071009 ; 090102 ;

摘要：

The transcriptional regulator Runx2 (runt-related transcription factor 2) has essential but distinct roles in os-teoblasts and chondrocytes in skeletal development. However, Runx2-mediated regulatory mechanisms un-derlying the distinctive programming of osteoblasts and chondrocytes are not well understood. Here, we perform an integrative analysis to investigate Runx2-DNA binding and chromatin accessibility ex vivo using neonatal osteoblasts and chondrocytes. We find that Runx2 engages with cell-type-distinct chromatin -accessible regions, potentially interacting with different combinations of transcriptional regulators, forming cell-type-specific hotspots, and potentiating chromatin accessibility. Genetic analysis and direct cellular re-programming studies suggest that Runx2 is essential for establishment of chromatin accessibility in osteo-blasts. Functional enhancer studies identify an Sp7 distal enhancer driven by Runx2-dependent binding and osteoblast-specific chromatin accessibility, contributing to normal osteoblast differentiation. Our findings provide a framework for understanding the regulatory landscape encompassing Runx2-mediated and cell -type-distinct enhancer networks that underlie the specification of osteoblasts.

引用

页数：27

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