因抗体结构发现而获1972年诺奖的Gerald M. Edelman, 于1988年初步勾画"拓扑生物学"理论框架, 解释生物多样性的发育和生长过程中的细胞表面分子与其他细胞分子（和/或基质）互作引起的位置依赖性调节，导致物种特异性组织模式和动物形式的不同细胞分化^[1]。直到最近16年，我们的科研积累——将该框架与分子细胞生物学、遗传学或表观遗传学进行了概念整合"拓扑生物学"，这一术语因此从形态发生扩展到膜蛋白拓扑结构，从信息流问题，到生物学中的基因调控，从而决定了细胞类型、以及差异组织和器官稳态的完整性。鉴于此，也称为拓扑遗传学。这一新扩展的拓扑生物学概念是由张义国及同事提出且被验证的^[2-11], 并获得了Mikhail Bogdanov与William Dowhan^[12], Gökhan S.Hotamisligil^[13], ElkeKrüger^[14]和Carolyn R. Bertozzi^[15]的认可。

 左图显示张义国原创工作与跨膜转录拓扑生物学理论模型，确定拓扑决定元^[2-7]。这些拓扑元确定Nrf1各功能域，在不同亚细胞区中定位与逆定位。值得注意的是，反式激活域(TADs)能动态逆转位——从内质网腔穿过脂膜到胞浆侧， 拓扑矢量加工——调控不同时空变化的连续的翻译后修饰和蛋白水解，产生不同或相反活性转录因子形式, 调控着细胞稳态、器官完整性、以及上皮细胞与间质细胞转化^[8,16]。

右图模型III显示我们的假说——拓扑调节性近膜蛋白Nrf1水解^[10], 完全不同于与模型I信号肽加工^[17] （由Günter Blobel发现并获得1999年诺奖） 和模型II ATF6和SREBP1调节性膜内蛋白水解^[18]（由王晓东大老板Goldstein和Brown (及其数千上万门徒)合作45年完成，他们早期发现胆固醇代谢机制而获1985年诺奖)。我们另一重大颠覆性发现，Nrf1D是存在于血浆中的第一个候选分泌型转录因子，其前体感受脂膜内外氧化还原(redox)状态^[19]。

Featured references:

1.       Edelman, G. M. (1988) Topobiolgy, An introduction to molecular embryology. Basic Books, A Subsidiary of Perseus Books, L.L.C. New York, 1-240

2.       Zhang, Y., Lucocq, J. M., Yamamoto, M., and Hayes, J. D. (2007) The NHB1 (N-terminal homology box 1) sequence in transcription factor Nrf1 is required to anchor it to the endoplasmic reticulum and also to enable its asparagine-glycosylation. Biochem J 408, 161-172

3.       Zhang, Y., Lucocq, J. M., and Hayes, J. D. (2009) The Nrf1 CNC/bZIP protein is a nuclear envelope-bound transcription factor that is activated by t-butyl hydroquinone but not by endoplasmic reticulum stressors. Biochem J 418, 293-310

4.       Zhang, Y., and Hayes, J. D. (2010) Identification of topological determinants in the N-terminal domain of transcription factor Nrf1 that control its orientation in the endoplasmic reticulum membrane. Biochem J 430, 497-510

5.       Zhang, Y., and Hayes, J. D. (2013) The membrane-topogenic vectorial behaviour of Nrf1 controls its post-translational modification and transactivation activity. Sci Rep 3; 2006, 1-16,

6.       Zhang, Y., Ren, Y., Li, S., and Hayes, J. D. (2014) Transcription factor Nrf1 is topologically repartitioned across membranes to enable target gene transactivation through its acidic glucose-responsive domains. PLoS One 9, e93458

7.       Zhang, Y., Li, S., Xiang, Y., Qiu, L., Zhao, H., and Hayes, J. D. (2015) The selective post-translational processing of transcription factor Nrf1 yields distinct isoforms that dictate its ability to differentially regulate gene expression. Sci Rep 5, 12983

8.       Zhang, Y., and Xiang, Y. (2016) Molecular and cellular basis for the unique functioning of Nrf1, an indispensable transcription factor for maintaining cell homoeostasis and organ integrity. Biochem J 473, 961-1000

9.       Yuan, J., Zhang, S., and Zhang, Y. (2018) Nrf1 is paved as a new strategic avenue to prevent and treat cancer, neurodegenerative and other diseases. Toxicol Appl Pharmacol 360, 273-283

10.     Xiang, Y., Halin, J., Fan, Z., Hu, S., Wang, M., Qiu, L., Zhang, Z., Mattjus, P., and Zhang, Y. (2018) Topovectorial mechanisms control the juxtamembrane proteolytic processing of Nrf1 to remove its N-terminal polypeptides during maturation of the CNC-bZIP factor. Toxicol Appl Pharmacol 360, 160-184

11.     Xiang, Y., Wang, M., Hu, S., Qiu, L., Yang, F., Zhang, Z., Yu, S., Pi, J., and Zhang, Y. (2018) Mechanisms controlling the multistage post-translational processing of endogenous Nrf1a/TCF11 proteins to yield distinct isoforms within the coupled positive and negative feedback circuits. Toxicol Appl Pharmacol 360, 212-235

12.     Mikhail Bogdanov, H. V., and William Dowhan. (2018) Flip-flopping membrane proteins: How the charge balance rule governs dynamic membrane protein topology. Biogenesis of Fatty Acids, Lipids and Membranes, edited by O. Geiger Springer International Publishing AG, part of Springer Nature 2018, 1-28

13.     Widenmaier, S. B., Snyder, N. A., Nguyen, T. B., Arduini, A., Lee, G. Y., Arruda, A. P., Saksi, J., Bartelt, A., and Hotamisligil, G. S. (2017) NRF1 is an ER membrane sensor that is central to cholesterol homeostasis. Cell 171, 1094-1109 e1015

14.     Steffen, J., Seeger, M., Koch, A., and Kruger, E. (2010) Proteasomal degradation is transcriptionally controlled by TCF11 via an ERAD-dependent feedback loop. Mol Cell 40, 147-158

15.     Tomlin, F. M., Gerling-Driessen, U. I. M., Liu, Y. C., Flynn, R. A., Vangala, J. R., Lentz, C. S., Clauder-Muenster, S., Jakob, P., Mueller, W. F., Ordonez-Rueda, D., Paulsen, M., Matsui, N., Foley, D., Rafalko, A., Suzuki, T., Bogyo, M., Steinmetz, L. M., Radhakrishnan, S. K., and Bertozzi, C. R. (2017) Inhibition of NGLY1 Inactivates the Transcription Factor Nrf1 and Potentiates Proteasome Inhibitor Cytotoxicity. ACS central science 3, 1143-1155

16.     Ren, Y., Qiu, L., Lü, F., Ru, X., Li, S., Xiang, Y., Yu, S., and Zhang, Y. (2016) TALENs-directed knockout of the full-length transcription factor Nrf1 alpha that represses malignant behaviour of human hepatocellular carcinoma (HepG2) cells. Scientific Reports, 2016, 6: 23775

17.     Blobel, G., and Dobberstein, B. (1975) Transfer of proteins across membranes. I. Presence of proteolytically processed and unprocessed nascent immunoglobulin light chains on membrane-bound ribosomes of murine myeloma. J Cell Biol 67, 835-851

18.     Brown, M. S., and Goldstein, J. L. (2012) Scientific side trips: six excursions from the beaten path. J Biol Chem 287, 22418-22435

19.     Yuan, J., Wang, H., Xiang, Y., Hu, S., Li, S., Wang, M., Qiu, L., and Zhang, Y. (2018) Nrf1D is the first candidate secretory transcription factor in the blood plasma, its precursor existing as a unique redox-sensitive transmembrane CNC-bZIP protein in hemopoietic and somatic tissues. Int J Mol Sci. 2018;19(10). pii: E2940.