A functional map of genomic HIF1α-DNA complexes in the eye lens revealed through multiomics analysis.
A functional map of genomic HIF1α-DNA complexes in the eye lens revealed through multiomics analysis.
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DOI：
10.1186/s12864-021-07795-9
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发表时间：
2021-07-03
期刊：
影响因子：
4.4
通讯作者：
Kantorow M
中科院分区：
文献类型：
--
作者：
Disatham J;Brennan L;Chauss D;Kantorow J;Afzali B;Kantorow M
在眼睛透镜发育期间，胚胎脉管系统退化，使得透镜没有直接的氧源。在胚胎期和整个成年期，透镜从表面到核心含有逐渐降低的氧梯度，其与未成熟表面上皮细胞向成熟核心透明纤维细胞的自然分化平行。透镜的这些特性表明低氧和低氧反应的主要调节因子低氧诱导转录因子1（HIF 1）在调节透镜纤维细胞分化、结构和透明度所需的基因中的潜在作用。本研究采用CUT&RUN、RNA-seq和ATACseq分析相结合的多组学方法，建立了透镜HIF 1 α结合位点、HIF 1 α激活或抑制基因以及HIF 1 α调控基因的染色质状态的基因组互补。CUT&RUN分析显示鸡透镜基因组中存在8375个HIF 1 α-DNA结合复合物。1190个HIF 1 α-DNA结合复合物在ATACseq鉴定的染色质可接近区域内显著聚集（χ2检验p < 1 × 10− 55）。HIF 1 α-DNA复合物的形成证实了526个基因的激活或抑制，其中116个基因在转录起始位点的10 kB范围内含有HIF 1 α结合位点。一些已鉴定的HIF 1 α基因先前已建立透镜功能，而另一些具有以前从未在透镜中研究过的新功能。GO和这些基因的通路分析表明，HIF 1 α参与控制对透镜纤维细胞形成、结构和功能可能至关重要的多种细胞通路，包括糖酵解、细胞周期调控、染色质重塑、Notch和Wnt信号传导、分化、发育和透明度。这些数据建立了眼透镜中基因组HIF 1 α-DNA复合物的第一个功能图谱。他们将HIF 1 α确定为多种基因的重要调节因子，这些基因先前被证明对透镜的形成和功能至关重要，并且他们揭示了HIF 1 α在多种基因的调节中的需求，这些基因尚未被检查用于透镜功能。它们支持在透镜纤维细胞形成、结构和功能中对HIF 1 α的需求，并为理解HIF 1 α在更复杂组织的发育、结构和功能中的潜在作用和需求提供了基础。在线版本包含补充材料，可通过10.1186/s12864-021-07795-9获得。
During eye lens development the embryonic vasculature regresses leaving the lens without a direct oxygen source. Both embryonically and throughout adult life, the lens contains a decreasing oxygen gradient from the surface to the core that parallels the natural differentiation of immature surface epithelial cells into mature core transparent fiber cells. These properties of the lens suggest a potential role for hypoxia and the master regulator of the hypoxic response, hypoxia-inducible transcription factor 1 (HIF1), in the regulation of genes required for lens fiber cell differentiation, structure and transparency. Here, we employed a multiomics approach combining CUT&RUN, RNA-seq and ATACseq analysis to establish the genomic complement of lens HIF1α binding sites, genes activated or repressed by HIF1α and the chromatin states of HIF1α-regulated genes. CUT&RUN analysis revealed 8375 HIF1α-DNA binding complexes in the chick lens genome. One thousand one hundred ninety HIF1α-DNA binding complexes were significantly clustered within chromatin accessible regions (χ2 test p < 1 × 10− 55) identified by ATACseq. Formation of the identified HIF1α-DNA complexes paralleled the activation or repression of 526 genes, 116 of which contained HIF1α binding sites within 10kB of the transcription start sites. Some of the identified HIF1α genes have previously established lens functions while others have novel functions never before examined in the lens. GO and pathway analysis of these genes implicate HIF1α in the control of a wide-variety of cellular pathways potentially critical for lens fiber cell formation, structure and function including glycolysis, cell cycle regulation, chromatin remodeling, Notch and Wnt signaling, differentiation, development, and transparency. These data establish the first functional map of genomic HIF1α-DNA complexes in the eye lens. They identify HIF1α as an important regulator of a wide-variety of genes previously shown to be critical for lens formation and function and they reveal a requirement for HIF1α in the regulation of a wide-variety of genes not yet examined for lens function. They support a requirement for HIF1α in lens fiber cell formation, structure and function and they provide a basis for understanding the potential roles and requirements for HIF1α in the development, structure and function of more complex tissues. The online version contains supplementary material available at 10.1186/s12864-021-07795-9.
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影响因子：
3.4
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