Martynova Elena, Bouchard Maxime, Musil Linda S, Cvekl Ales
Departments of Ophthalmology and Visual Sciences and Genetics, Albert Einstein College of Medicine, Bronx, New York.
Goodman Cancer Research Centre and Department of Biochemistry, McGill University, Montreal, Quebec, Canada.
Dev Dyn. 2018 Nov;247(11):1186-1198. doi: 10.1002/dvdy.24677. Epub 2018 Nov 10.
The tissue-specific transcriptional programs during normal development require tight control by distal cis-regulatory elements, such as enhancers, with specific DNA sequences recognized by transcription factors, coactivators, and chromatin remodeling enzymes. Gata3 is a sequence-specific DNA-binding transcription factor that regulates formation of multiple tissues and organs, including inner ear, lens, mammary gland, T-cells, urogenital system, and thyroid gland. In the eye, Gata3 has a highly restricted expression domain in the posterior part of the lens vesicle; however, the underlying regulatory mechanisms are unknown.
Here we describe the identification of a novel bipartite Gata3 lens-specific enhancer located ∼18 kb upstream from its transcriptional start site. We also found that a 5-kb Gata3 promoter possesses low activity in the lens. The bipartite enhancer contains arrays of AP-1, Ets-, and Smad1/5-binding sites as well as binding sites for lens-associated DNA-binding factors. Transient transfection studies of the promoter with the bipartite enhancer showed enhanced activation by BMP4 and FGF2.
These studies identify a novel distal enhancer of Gata3 with high activity in lens and indicate that BMP and FGF signaling can up-regulate expression of Gata3 in differentiating lens fiber cells through the identified Gata3 enhancer and promoter elements. Developmental Dynamics 247:1186-1198, 2018. © 2018 The Authors. Developmental Dynamics published by Wiley Periodicals, Inc. on behalf of American Association of Anatomists.
正常发育过程中的组织特异性转录程序需要由远端顺式调控元件（如增强子）进行严格控制，这些元件具有特定的DNA序列，可被转录因子、共激活因子和染色质重塑酶识别。Gata3是一种序列特异性DNA结合转录因子，可调节包括内耳、晶状体、乳腺、T细胞、泌尿生殖系统和甲状腺在内的多种组织和器官的形成。在眼睛中，Gata3在晶状体泡后部具有高度受限的表达域；然而，其潜在的调控机制尚不清楚。
在此，我们描述了一个新的二分体Gata3晶状体特异性增强子的鉴定，该增强子位于其转录起始位点上游约18 kb处。我们还发现5 kb的Gata3启动子在晶状体中活性较低。二分体增强子包含AP-1、Ets和Smad1/5结合位点阵列以及与晶状体相关的DNA结合因子的结合位点。启动子与二分体增强子的瞬时转染研究表明，BMP4和FGF2可增强其激活作用。
这些研究鉴定了一个在晶状体中具有高活性的新的Gata3远端增强子，并表明BMP和FGF信号可通过已鉴定的Gata3增强子和启动子元件上调分化中的晶状体纤维细胞中Gata3的表达。《发育动力学》2018年第247卷：1186 - 1198页。© 2018作者。由Wiley Periodicals, Inc.代表美国解剖学家协会出版的《发育动力学》。
