人体基因组拥有超过30亿对碱基序列，但仅有约1.5%的序列拥有蛋白质编码功能，其余大部分非编码核酸序列的功能尚不清楚。我的研究主要致力于通过组学新方法开发、系统生物学与生物信息学综合应用来探索这些非编码核酸序列的分子功能。非编码基因组一般通过两种方式发挥作用：1）作为顺式调控元件，结合调控蛋白质，直接发挥调控功能；2）转录为非编码RNA，以RNA的形式参与重要的生理生化调控。我的研究也从这两方面分别入手，开展工作：

（1）有功能的非编码DNA主要集中于一些顺式调控元件，例如增强子、启动子上，通过结合转录因子等反式元件发挥转录调控等功能。对于直接参与顺式调控的非编码DNA的功能研究，我们主要采取分析它们对转录因子蛋白结合差异及其对下游目标基因表达的影响，以解析它们在人类遗传疾病中的分子功能。我们发明的SNP-SELEX技术，利用高通量手段量化分析非编码DNA与转录因子相互作用。

（2）转录形成的非编码RNA，往往通过与胞内蛋白质相互作用参与调控，例如过量的非编码RNA与调控蛋白质结合后，起到类似于海绵吸水的作用，导致调控蛋白无法达到调控部位而丧失功能；或者非编码RNA作为介质分子，把无法直接相互作用的蛋白质分子串联到一起形成复合体发挥作用。基于此，我们主要通过比较的办法，寻找不同情况下有表达差异或不同富集程度的非编码RNA、鉴定这些非编码RNA的相互作用蛋白质等方法对其功能进行深入细致的探索。

代表性论文 (# 标注通讯作者; * 标注共同第一作者):

2021年

·       J. Yan#,*, Y. Qiu*, A. dos Santos*, Y. Yin, Yang E. Li, N. Vinckier, N. Nariai, P. Benaglio, A. Raman, X. Li, S. Fan, J. Chiou, F. Chen, K.A. Frazer, K.J. Gaulton, M. Sander, J. Taipale#, B. Ren#, Systematic analysis of binding of transcription factors to noncoding variants, Nature 591 (2021) 147-151.

·       T. Wang*, W. Sun*, L. Fan*, C. Hua*, N. Wu, S. Fan, J. Zhang, X. Deng#, J. Yan#, An atlas of the binding specificities of transcription factors in Pseudomonas aeruginosa directs prediction of novel regulators in virulence, eLife 10 (2021) e61885.

·       D.S. Tan*, Y. Chen*, Y. Gao, A. Bednarz, Y. Wei, V. Malik, D. HH Ho, M. Weng, S. Y. Ho, Y. Srivastava, S. Velychko, X. Yang, L. Fan, J. Kim, J. Graumann, G. D Stormo, T. Braun, J. Yan, H. R Schöler, R. Jauch#. Directed evolution of an enhanced POU reprogramming factor for cell fate engineering, Molecular Biology and Evolution 38(7) (2021) 2854-2868.

·       R.J. Geusz*, A. Wang*, J. Chiou*, J.J. Lancman*, N. Wetton, S. Kefalopoulou, J. Wang, Y. Qiu, J. Yan, A. Aylward, B. Ren, P. DS Dong, K. J Gaulton#, M. Sander#, Pancreatic progenitor epigenome maps prioritize type 2 diabetes risk genes with roles in development, eLife 10 (2021) e59067.

2020年

·       W. Yi*, J. Li*, X. Zhu*, X. Wang*, L. Fan, W. Sun, L. Liao, J. Zhang, X. Li, J. Ye, F. Chen, J. Taipale, K.M. Chan#, L. Zhang#, J. Yan#, CRISPR-assisted detection of RNA-protein interactions in living cells, Nature Methods 17(7) (2020) 685-688.

·       L. Fan, T*. Wang*, C. Hua*, W. Sun*, X. Li, L. Grunwald, J. Liu, N. Wu, X. Shao, Y. Yin, J. Yan#, X. Deng#, A compendium of DNA-binding specificities of transcription factors in Pseudomonas syringae, Nature Communications 11(1) (2020) 4947.

·       J. Yan#, X. Wang, Detection of Disease-associated Mutations and Biomarkers Using Next-generation Sequencing, Detection Methods Precision Medicine 18, (2021) 119. (book chapter)

·       Z. Wang*, Y. Li*, B. Hou*, M.I. Pronobis*, M. Wang, Y. Wang, G. Cheng, W. Weng, Y. Wang, Y. Tang, X. Xu, R. Pan, F. Lin, N. Wang, Z. Chen, S. Wang, L. z Ma, Y. Li, D. Huang, L. Jiang, Z. Wang, W. Zeng, Y. Zhang, X. Du, Y. Lin, Z. Li, Q. Xia, J. Geng, H. Dai, Y. Yu, X. Zhao, Z. Yuan, J. Yan, Q. Nie, X. Zhang, K. Wang, F. Chen, Q. Zhang, Y. Zhu, S. Zheng, K. D Poss, S. Tao#, X. Meng#, An array of 60,000 antibodies for proteome-scale antibody generation and target discovery, Science Advances 6 (11) (2020) eaax2271.

2019年

·       X. Wang#, M.J. Cairns, J. Yan#, Super-enhancers in transcriptional regulation and genome organization, Nucleic Acids Research 47(22) (2019) 11481-11496.

·       W.W. Greenwald*, J. Chiou*, J. Yan*, Y. Qiu*, N. Dai*, A. Wang, N. Nariai, A. Aylward, J.Y. Han, N. Kadakia, N. Barrufet, M. Okino, F. Drees, N. Vinckier, L. Minichiello, D. Gorkin, J. Avruch, K. Frazer, M. Sander, B. Ren, K.J. Gaulton#, Pancreatic islet chromatin accessibility and conformation defines distal enhancer networks of type 2 diabetes risk, Nature Communications 10 (2019) 2078.

2018年或更早 (仅选取代表性成果)

·       J. Yan*, S.A. Chen*, A. Local, T. Liu, Y. Qiu, K.M. Dorighi, S. Preissl, C.M. Rivera, C. Wang, Z. Ye, K. Ge, M. Hu, J. Wysocka, B. Ren#, Histone H3 lysine 4 monomethylation modulates long-range chromatin interactions at enhancers, Cell Research 28(2) (2018) 204-220.

·       Y. Yin, E. Morgunova, A. Jolma, E. Kaasinen, B. Sahu, S. Khund-Sayeed, P.K. Das, T. Kivioja, K. Dave, F. Zhong, K.R. Nitta, M. Taipale, A. Popov, P.A. Ginno, S. Domcke, J. Yan, D. Schubeler, C. Vinson, J. Taipale#, Impact of cytosine methylation on DNA binding specificities of human transcription factors, Science 356(6337) (2017).

·       Q. Huang*, T. Whitington*, P. Gao, J.F. Lindberg, Y. Yang, J. Sun, M.R. Väisänen, R. Szulkin, M. Annala, J. Yan, L.A. Egevad, K. Zhang, R. Lin, A. Jolma, M. Nykter, A. Manninen, F. Wiklund, M.H. Vaarala, T. Visakorpi, J. Xu, J. Taipale#, G. Wei#. A prostate cancer susceptibility allele at 6q22 increases RFX6 expression by modulating HOXB13 chromatin binding, Nature Genetics 46(2) (2014) 126-35.

·       J. Yan*, M. Enge*, T. Whitington, K. Dave, J. Liu, I. Sur, B. Schmierer, A. Jolma, T. Kivioja, M. Taipale, J. Taipale#, Transcription factor binding in human cells occurs in dense clusters formed around cohesin anchor sites, Cell 154(4) (2013) 801-813.

·       A. Jolma*, J. Yan*, T. Whitington, J. Toivonen, K.R. Nitta, P. Rastas, E. Morgunova, M. Enge, M. Taipale, G. Wei, K. Palin, J.M. Vaquerizas, R. Vincentelli, N.M. Luscombe, T.R. Hughes, P. Lemaire, E. Ukkonen, T. Kivioja, J. Taipale#, DNA-binding specificities of human transcription factors, Cell 152(1-2) (2013) 327-339.

·       I.K. Sur, O. Hallikas, A. Vaharautio, J. Yan, M. Turunen, M. Enge, M. Taipale, A. Karhu, L.A. Aaltonen, J. Taipale#, Mice lacking a Myc enhancer that includes human SNP rs6983267 are resistant to intestinal tumors, Science 338(6112) (2012) 1360-3.

·       N. Makinen, M. Mehine, J. Tolvanen, E. Kaasinen, Y. Li, H.J. Lehtonen, M. Gentile, J. Yan, M. Enge, M. Taipale, M. Aavikko, R. Katainen, E. Virolainen, T. Bohling, T.A. Koski, V. Launonen, J. Sjoberg, J. Taipale, P. Vahteristo, L.A. Aaltonen#, MED12, the mediator complex subunit 12 gene, is mutated at high frequency in uterine leiomyomas, Science 334(6053) (2011) 252-5.

·       S. Tuupanen, M. Turunen, R. Lehtonen, O. Hallikas, S. Vanharanta, T. Kivioja, M. Björklund, G. Wei, J. Yan, I. Niittymäki, J. Mecklin, H. Järvinen, A. Ristimäki, M. Di-Bernardo, P. East, L. Carvajal-Carmona, R.S. Houlston, I. Tomlinson, K. Palin, E. Ukkonen, A. Karhu, J. Taipale#, L.A. Aaltonen#. The common colorectal cancer predisposition SNP rs6983267 at chromosome 8q24 confers potential to enhanced Wnt signaling, Nature Genetics 41(8) (2009) 885-90.