Integration and Evolution of Hypoxia Response Network---Systems Biology and Evolution Approach (II)

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Project title

Code/計畫編號

NSC103-2627-B019-001

Translated Name/計畫中文名

低氧訊息網路的系統與演化生物學研究---斑馬魚低氧訊息網路系統的生物功能(總計畫及子計畫1)(II)

Project Coordinator/計畫主持人

Chin-Hwa Hu

Funding Organization/主管機關

National Science and Technology Council

Department/Unit

Department of Bioscience and Biotechnology

Website

https://www.grb.gov.tw/search/planDetail?id=8361222

Year

2014

Start date/計畫起

01-08-2014

Expected Completion/計畫迄

01-07-2015

Bugetid/研究經費

2680千元

ResearchField/研究領域

生物技術(理)
生物科學

當細胞進行有氧代謝時，會藉由電子傳遞鏈提供生物能量，而當遇到低氧逆境情況時，細胞會藉由低氧訊息系統，感應到缺氧的情況，進而改變細胞內的生理代謝與基因調控路徑。本計畫整合基因蛋白體學、代謝體學、發育生物學與生物資訊學等各項核心技術，深入探討細胞低氧訊息系統在正常狀態的斑馬魚和海膽胚胎中可能扮演的各種角色。在本計畫（子計畫一）中我們分別從下列四個角度去探討低氧訊息在胚胎發育中扮演的角色：從基因體學探討胚胎內Hif1α與Fα在常氧環境下的生理功能以及在低氧環境下的防禦與干擾作用；低氧敏感性基因在常氧環境下的生物功能以及對Hif1α與Fα的專一依賴性；利用生物資訊分析搜尋高保守性低氧敏感基因及其分子演化路徑；4. 胚胎內Hif1α與Hif2α活性的調控。針對上述的研究工作我們在第二年的工作裡獲得一些突破性的發展： 1. 首先我們發現Hif1α與Hif2α分別在紅血球與神經和肝臟發育有密切的關係。尤其在紅血球發育方面，我們發現Hif1α不僅是低氧環境壓力誘發紅血球增生的關鍵因子，更在紅血球發育過程中促進血球幹細胞內’GATA因子轉換（GATA switch)”扮演了重要的功能，藉以讓紅血球的分化得以完成。 2. 我們的研究發現Hif2α控制腦細胞中Notch訊息系統的活性以及epo的表現，將Hif2α弱化會造成一系列notch基因的表現受到影響，並且連帶使得下游基因如her4等基因的表現明顯減少。 3. 我們發現在早期胚胎發育期間會在中樞神經與造血細胞中呈現短暫性缺氧的狀態，而在稍後的胚胎內則回復到常氧的情況，顯示在特定發育時期部分組織細胞可能因缺氧的狀況出現無氧代謝作用，而在較晚期的胚胎內恢復常氧狀態後細胞內的代謝轉換成有氧代謝。 4. 我們利用NGS RNA seq分析了正常胚胎與弱化Hif1α、GATA1或Hif2α、Birc5a胚胎的基因轉錄體（transcriptome）全基因組的相對表現量，並進行基因關聯性的分析，發現Hif1α及GATA1分別參與了神經、紅血球與免疫補體系統的發育及活性。未來我們將繼續前述未完成的工作，並將把研究重點放在下列幾項工作上，包括：探討Hif1α在紅血球發育上扮演的角色、Hif2α-Birc5a-Epo間在神經細胞分化上的關聯性以及與造血系統的互動、胚胎發育時期低氧訊號的產生與代謝途徑的轉換、Hif2α對Notch細胞訊息的影響、從NGS分析低氧訊息系統在胚胎中所扮演的功能，並將與其他子計畫合作、分享NGS資料，比較海膽與斑馬魚胚胎發育期間低氧訊息調控路徑的異同以及在胚胎發育中所扮演的角色。我們預期這些研究將會幫助我們更深入的了解低氧訊息路徑在胚胎發育中的生物功能。 Oxygen provides pivotal biological energy through an aerobic respiration system. To adapt hypoxia stress, vertebrate will make some physiological changes, such as metabolic switch, anaerobic respiration change, enhancing metabolic efficiency, increasing erythropoietic and angiogenic processes as well as inhibiting apoptosis through hypoxia-signaling systems. Most of cellular hypoxia-responses are mediated by hypoxia-inducible factors (HIFs) to mediate its downstream gene transcriptions. Nevertheless, the physiological function of HIFs in normal growth cell has not been investigated yet. Here we would like to investigate the functions of cellular hypoxia-signaling system in the developing embryos. During the second year, we focused on the following themes: Biological functions of Hif1α and Hif2α in the developing embryos, 2. Target-selectivity of Hif1α and Hif2α, 3. Functional conservation of Hif1α and Hif2α-targeted genes, 4. Regulation of Hif1α and Hif2α activities during development. Here we present a summary of our current progress toward this goal. Firstly, we found that Hif1α and Hif2α play critical roles in erythropoiesis and neural differentiation. Specifically, Hif1α is required for GATA switch during erythrocyte maturation. Our results also demonstrated that Hif2α modulates both Notch signaling system and epo transcription. Depletion of Hif2α resulted in suppression of transcriptions of a serial of notch members and their downstream target gene, such as her4 members. By using TPZ as a ROS mediator, we have revealed temporal hypoxia niches in CNS and ICM areas that were generated during early stages of development. As revealed by NGS RNA seq analyses, we found that Hif1α及GATA1 have critical functions in neuron and erythrocyte differentiation and complement system activities. In next year, we will continue previous studies and focus on the following topics, such as the function of Hif1α in erythropoiesis, the functions of Hif2α-Birc5a-Epo in neural differentiation, hypoxia niche in embryos and metabolic switch, influence of Hif2α in Notch family, and the conservation of hypoxia signals in sea urchin and zebrafish development. This study will shed light on understanding the biological functions of hypoxia signaling in embryos and cancer cells.

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Integration and Evolution of Hypoxia Response Network---Systems Biology and Evolution Approach (II)

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