Department of Genetics, Blavatnik Institute; Harvard Medical School, Boston, MA 02115, USA.
Department of Ophthalmology, Blavatnik Institute; Harvard Medical School, Boston, MA 02115, USA.
Development. 2021 May 1;148(9). doi: 10.1242/dev.198549. Epub 2021 Apr 30.
The vertebrate retina is generated by retinal progenitor cells (RPCs), which produce >100 cell types. Although some RPCs produce many cell types, other RPCs produce restricted types of daughter cells, such as a cone photoreceptor and a horizontal cell (HC). We used genome-wide assays of chromatin structure to compare the profiles of a restricted cone/HC RPC and those of other RPCs in chicks. These data nominated regions of regulatory activity, which were tested in tissue, leading to the identification of many cis-regulatory modules (CRMs) active in cone/HC RPCs and developing cones. Two transcription factors, Otx2 and Oc1, were found to bind to many of these CRMs, including those near genes important for cone development and function, and their binding sites were required for activity. We also found that Otx2 has a predicted autoregulatory CRM. These results suggest that Otx2, Oc1 and possibly other Onecut proteins have a broad role in coordinating cone development and function. The many newly discovered CRMs for cones are potentially useful reagents for gene therapy of cone diseases.
脊椎动物的视网膜是由视网膜祖细胞（RPCs）产生的，这些细胞可以产生超过 100 种细胞类型。虽然一些 RPC 可以产生多种细胞类型，但其他 RPC 只能产生特定类型的子细胞，例如视锥细胞和水平细胞（HC）。我们使用全基因组染色质结构分析来比较小鸡中一种受限的视锥/HC RPC 和其他 RPC 的图谱。这些数据提名了具有调控活性的区域，这些区域在组织中进行了测试，从而鉴定出许多在视锥/HC RPC 和发育中的视锥细胞中活跃的顺式调控模块（CRMs）。发现两个转录因子 Otx2 和 Oc1 与许多这些 CRM 结合，包括那些靠近对视锥细胞发育和功能很重要的基因的 CRM，它们的结合位点对于活性是必需的。我们还发现 Otx2 具有一个预测的自身调控 CRM。这些结果表明，Otx2、Oc1 以及可能的其他 Onecut 蛋白在协调视锥细胞发育和功能方面具有广泛的作用。许多新发现的视锥细胞 CRM 可能是视锥细胞疾病基因治疗的有用试剂。
