多学科合作、融合在化学生物学发展中的重要作用

1、时间时间会议名称会议名称2002年年全国化学生物学发展战略研讨会全国化学生物学发展战略研讨会2003年年化学生物学研究领域讨论会化学生物学研究领域讨论会2004年年香山会议：香山会议：“化学生物学驱动的功能基因组和创性药物研究化学生物学驱动的功能基因组和创性药物研究”2005年年第第40届届IUPAC大会的化学生物学分会大会的化学生物学分会2005年年双清论坛双清论坛:“医学基因组和创新药物研究导向的化学生物学医学基因组和创新药物研究导向的化学生物学”2006年年化学生物学综合交叉研究领域化学生物学综合交叉研究领域”小型讨论会小型讨论会 2004年、年、2006年年中德青年科学家化学生物学研讨

2、会中德青年科学家化学生物学研讨会2007年年中中-美化学生物学专题讨论会美化学生物学专题讨论会自自2001年起年起每两年一次每两年一次全国化学生物学学术会议全国化学生物学学术会议（至今已举办过七届，第八届将于（至今已举办过七届，第八届将于2013年年9月在上海举行。月在上海举行。每一届的参会代表人数均有大幅增长）。每一届的参会代表人数均有大幅增长）。自自2005年起年起每年一次每年一次中美华人化学教授会议中美华人化学教授会议（设有机化学和化学生物学两个主题，至今已举办过九届，）（设有机化学和化学生物学两个主题，至今已举办过九届，）Focused Areas in NIH Directors N

3、ew Innovator Program1Behavioral and Social Science2Chemical Biology3Clinical and Translational Research 4Immunology 5Instrumentation and Engineering6Molecular and Cellular Biology7Neuroscience8High Throughput and Integrative Biology9Quantitative and Computational Biology2004美国美国NIH Directors New Inn

4、ovator Program重点资助的方向重点资助的方向 英国政府对化学生物学的资助主要集中在资助包括化学领域英国政府对化学生物学的资助主要集中在资助包括化学领域EPSRC(Engineering and Physical Sciences Research Council).中国自然科学基金委在与人类健康相关领域的经费投入情况中国自然科学基金委在与人类健康相关领域的经费投入情况 (2004-2008； 摘自摘自Nature Chemical Biology, 2006, 4, 515-518)国家自然科学基金委重大研究计划国家自然科学基金委重大研究计划“基于化学小分子探针的信号转导过程研究基

5、于化学小分子探针的信号转导过程研究”（2007-2015）2007-2011， 申请书共计申请书共计607份份 (培育项目培育项目540份，重点项目份，重点项目67份份)。正式资助项目正式资助项目124项，其中培育项目项，其中培育项目110项，重点项目项，重点项目14项项 。已资助总经费为已资助总经费为9750万，占总预算万，占总预算65%。2012年重大研究计划共进行了首批年重大研究计划共进行了首批6个集成方向和团队的资助，个集成方向和团队的资助，2013年公布了第二批年公布了第二批3个项目个项目，总经费为总经费为5000万万，占总预算占总预算65%“基于化学小分子探针的信号转导过程研究基于

6、化学小分子探针的信号转导过程研究” (2007-2014)正式资助项目正式资助项目124项项:培育项目培育项目110项项重点支持项目重点支持项目14项）项）集成项目集成项目:第一批第一批 6 项项第二批第二批 3 项项Chemical biology in China Generation of chemical probes for studying signal transduction Development of new techniques and methods for detecting the information of signaling processes Biomark

7、er, target and lead discovery based on signal transduction processes Signaling mechanisms of cellular functions based on chemical small molecules下一步我国化学生物学要做什么？下一步我国化学生物学要做什么？Hot points in Chemical Biology Bioorthogonal Reactions Tracking single molecules at work in living cells Modification of Enha

8、ncer Chromatin Posttranscriptional RNA Modifications Small Molecules for Cell Reprogramming The Challenge and Promise of Glycomics Synthetic biology SYSTEMS BIOLOGY Measurement and modeling approaches bring a big-picture view of biology MAKING CONNECTIONS This network graph shows causal connections

9、among 30,512 genes, 31,459 proteins, and 5,824 small molecules in Genstructs model, which contains 136,362 causal connections that can be evaluated to explain the molecular state changes observed in large-scale systems biology experiments. The red connections represent inhibitions; green, activation

10、; light blue, reaction; dark blue, a product; yellow, catalysis; orange, binding; and black, gene product relations.Bioorthogonal Reactions for Labeling Biomolecules* The reactants in a bioorthogonal reaction should be kinetically, thermodynamically, and metabolically stable before the reaction take

11、s place and not toxic to living systems.* The reaction should yield stable covalent linkages with no or innocuous by products, rapid reactions with high second-order rate constants.* The two bioorthogonal moieties have to react selectively with each other under physiological conditions (ambient temp

12、erature and pressure, neutral pH, aqueous conditions), without either of them cross-reacting with the plethora of chemical functionalities found in living cells.ACS Chem. Biol. 2014, 9, 1620Tracking single molecules at work in living cellsMethods for imaging and tracking single molecules conjugated

13、with fluorescent probes, called single-molecule tracking (SMT), are now providing researchers with the unprecedented ability to directly observe molecular behaviors and interactions in living cells.nature chemical biology | VOL 10, 524 | JULY 2014 |Epigenetic Studies DNA Methylation and Demethylatio

14、n Hestone Acetylation and Deacetylation Noncoding RNA EnhancerEnhancer DNA, commonly 200500 bp in length, contains clustered recognition sites for multiple TFs, representing distinct classes of DNA bindersEnhancers play a central role in driving cell-type-specific gene expression and are capable of

15、activating transcription of their target genes at great distancesRecent large-scale epigenomic mapping revealed unexpected complexity and dynamics of enhancer utilization patterns, with 400,000 putative human enhancers annotated by the ENCODE project alone.Epigenetic Features of Active,Primed, and P

16、oised Enhancers(A) Schematic representation of the major chromatinfeatures found at active enhancers. Enhancers are associated with incorporation of hypermobile nucleosomes containing H3.3/H2A.Z histone variants, which compete for DNA binding with TFs. TFs in turn recruit coactivator proteins that c

17、an modify and remodel nucleosomes. H3K4me1 and H3K27ac are the predominant histone modifications deposited at nucleosomes flanking enhancer elements.(B) Prior to activation, enhancers can exist ina primed state, characterized by the presence ofH3K4me1. Other features that have been associatedwith en

18、hancer priming are presence of pioneerTFs, hypermobile H3.3/H2A.Z nucleosomes, DNA5mC hypomethylation, and hydroxylation (5hmC).(C) Schematic representation of the chromatinlandscape surrounding poised enhancers found inhuman and mouse ESCs. A subset of primedenhancers in ESCs is also marked by H3K2

19、7me3and associated with PRC2. These enhancers arebound by TFs and coactivators and communicatewith their target promotersMolecular Cell 49, 825，March 7, 2013Writers, Readers, and Erasers of,Major Enhancers MarksProteins capable of adding (writers), removing (erasers), and recognizing (readers) major

20、enhancer-associated chromatin modifications, including H3K4me1, H3K9ac, H3K27ac, and5hmC, are shown.DNA Methylation at Enhancers: Driver or Passenger?(1) DNA methylation plays an active role in shaping enhancer landscapes via eviction of TFs from theircognate sites (2) TFs are drivers of hypomethyla

21、ted states, whereas DNA methylation passively fills in sites vacated by TFs departed from decommissioned enhancers. （3）A couple of recent reports argue in favor of the second scenario5-Hydroxymethylcytosine 5hmC has been detected in genomes of several cell types, including ESCs, where it positively

22、correlates with gene activity and is found at promoters, gene bodies, and enhancers With respect to the latter elements and in contrast to 5mC, 5hmC coincides with H3K4me1 and H3K27ac and follows active enhancer marks during differentiation A recent report provided the first single-base-resolution 5

23、hmC map in mouse and human ESCs,revealing that 5hmC is most abundant at both poised and active enhancers, rather than at CpG-rich promoters, as previously suggestedHypermodifications at Positions 34 and 37 in the Anticodon LoopPositions 34 and 37 of the anticodon loop undergo by far the largest dive

24、rsity of posttranscriptional modifications. Highlighted are modified uridines (upper left panel) and guanosines (lower left panel), ubiquitous hypermodifications ensuring correct decoding at the wobble position. Sophisticated purine modifications found at position 37 (upper and lower right panels) p

25、lay roles in reading frame maintenance(A) Adenosine modifications resulting from conjugation to ubiquitous electrophilic metabolites.(B) Chemically sophisticated hypermodifications discovered throughout the past five decades. The year of publication is given in parentheses.(C) The C5-modified cytidi

26、nes related to so-called epigenetic DNA modifications recently discovered. ac6A, 6-acetyladenosine; Arp, 20-O-ribosyladenosine phosphate; oQ, epoxyqueuosine; tm5U, 5-taurinomethyluridine; nm5ges2U, 5-aminomethyl-2-geranyluridine; ho5C, 5-hydroxycytidine; f5C, 5-formyluridineProbing and Perturbing St

27、em Cells with Chemical Biology Murine somatic cells can be“reprogrammed” into induced pluripotent stem cells (iPSCs) with a specific set of transcription factors (TFs), namely, Oct4, Sox2, Klf4, and c-Myc (OSKM) The search of small molecules to improve and/or enable cell reprogramming toward pluripo

28、tency has been most fruitful. During reprogramming, somatic cells must undergo significant epigenetic changes (i.e., histone modifications and DNA methylation) to adopt the ESC-like patterns, small molecules modulating activities of enzymes involved in epigenetic modifications can, therefore, exert

29、profound effects on cell reprogramming. Small Molecules Replacing TFs in the Reprogramming of Somatic Cellssmall molecules combination starting cells TFs required VPA MEFs OSK BIX, BayK or RG108 MEFs OK Kenpaullone MEFs OSM E-616542 MEFs OKM A83-01, AMI-5 MEFs O VPA, CHIR, E-616542, Parnate MEFs O V

30、PA, CHIR, E-616542, Parnate, Forskolin, DZNep MEFs none VPA primary human fibroblast OS CHIR, Parnate human keratinocytes OK NaB, A83-01, PS48, PD neonatal human epidermal keratinocytes O Using cocktails of functionally diverse small molecules to synergistically improve cell reprogramming has been h

31、ighly fruitful. ACS Chem. Biol. 2014, 9, 3444Small Molecules for Cell Reprogramming and Heart Repair: Progress and PerspectiveMin Xie, Nan Cao, and Sheng Ding*ACS Chem. Biol. 2014, 9, 3444The Challenge and Promise of GlycomicsGlycomics is a broad and emerging scientific discipline focused on definin

32、g the structures and functional roles of glycans in biological systems. The staggering complexity of the glycome, minimally defined as the repertoire of glycans expressed in a cell or organism, has resulted in many challenges that must be overcome; these are being addressed by new advances in mass s

33、pectrometry as well as by the expansion of genetic and cell biology studies. Conversely, identifying the specific glycan recognition determinants of glycan-binding proteins by employing the new technology of glycan microarrays is providing insights into how glycans function in recognition and signal

34、ing within an organism and with microbes and pathogens.The promises of a more complete knowledge of glycomes are immense in that glycan modifications of intracellular and extracellular proteins have critical functions in almost all biological pathways.mutations of genes involved in specific glycosylation pathways of anabolism or catabolism might have little effect on cultured cells, but they a