A conserved transcription factor regulatory program promotes tendon fate,Developmental Cell

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A conserved transcription factor regulatory program promotes tendon fate
Developmental Cell ( IF 10.7 ) Pub Date : 2024-08-30 , DOI: 10.1016/j.devcel.2024.08.006
Xubo Niu ₁ , Delmy L Melendez ₂ , Suyash Raj ₂ , Junming Cai ₂ , Dulanjalee Senadeera ₂ , Joseph Mandelbaum ₃ , Ilya A Shestopalov ₃ , Scott D Martin ₄ , Leonard I Zon ₅ , Thorsten M Schlaeger ₃ , Lick Pui Lai ₆ , Andrew P McMahon ₆ , April M Craft ₇ , Jenna L Galloway ₈

Affiliation

Center for Regenerative Medicine, Department of Orthopaedic Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA.
Department of Orthopaedic Surgery, Boston Children's Hospital, Harvard Medical School, Boston, MA 02115, USA.
Division of Hematology/Oncology, Boston Children's Hospital, Harvard Medical School, Boston, MA 02115, USA.
Department of Sports Medicine, Massachusetts General Hospital, Boston, MA 02114, USA.
Division of Hematology/Oncology, Boston Children's Hospital, Harvard Medical School, Boston, MA 02115, USA; Howard Hughes Medical Institute, Boston, MA, USA; Harvard Stem Cell Institute, Cambridge, MA 02138, USA.
Department of Stem Cell Biology and Regenerative Medicine, Eli and Edythe Broad Center for Regenerative Medicine and Stem Cell Research, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA.
Department of Orthopaedic Surgery, Boston Children's Hospital, Harvard Medical School, Boston, MA 02115, USA; Harvard Stem Cell Institute, Cambridge, MA 02138, USA.
Center for Regenerative Medicine, Department of Orthopaedic Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA; Harvard Stem Cell Institute, Cambridge, MA 02138, USA.

Tendons, which transmit force from muscles to bones, are highly prone to injury. Understanding the mechanisms driving tendon fate would impact efforts to improve tendon healing, yet this knowledge is limited. To find direct regulators of tendon progenitor emergence, we performed a zebrafish high-throughput chemical screen. We established forskolin as a tenogenic inducer across vertebrates, functioning through Creb1a, which is required and sufficient for tendon fate. Putative enhancers containing cyclic AMP (cAMP) response elements (CREs) in humans, mice, and fish drove specific expression in zebrafish cranial and fin tendons. Analysis of these genomic regions identified motifs for early B cell factor (Ebf/EBF) transcription factors. Mutation of CRE or Ebf/EBF motifs significantly disrupted enhancer activity and specificity in tendons. Zebrafish ebf1a/ebf3a mutants displayed defects in tendon formation. Notably, Creb1a/CREB1 and Ebf1a/Ebf3a/EBF1 overexpression facilitated tenogenic induction in zebrafish and human pluripotent stem cells. Together, our work identifies the functional conservation of two transcription factors in promoting tendon fate.

中文翻译：

保守的转录因子调节程序促进肌腱命运

肌腱将力从肌肉传递到骨骼，极易受伤。了解驱动肌腱命运的机制将影响改善肌腱愈合的努力，但这些知识是有限的。为了找到肌腱祖细胞出现的直接调节因子，我们进行了斑马鱼高通量化学筛选。我们确定毛喉素是脊椎动物的肌腱诱导剂，通过 Creb1a 发挥作用，这是肌腱命运所必需的。在人类、小鼠和鱼类中含有环状 AMP （cAMP）反应元件（CRE）的推定增强子在斑马鱼颅肌腱和鳍肌腱中驱动特异性表达。对这些基因组区域的分析确定了早期 B 细胞因子（Ebf/EBF）转录因子的基序。CRE 或 Ebf/EBF 基序突变显着破坏了肌腱中的增强子活性和特异性。斑马鱼 ebf1a/ebf3a 突变体表现出肌腱形成缺陷。值得注意的是，Creb1a/CREB1 和 Ebf1a/Ebf3a/EBF1 过表达促进了斑马鱼和人多能干细胞的肌腱诱导。总之，我们的工作确定了两种转录因子在促进肌腱命运中的功能保守性。

更新日期：2024-08-30

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