A two-day international scientific symposium to celebrate the 70th anniversary of the discovery of DNA's double helix structure, the most profound biological discovery of the last century, concluded in Beijing on Oct 22, 2023.
The symposium, which also marked the third anniversary of Changping Laboratory, focused on recent advances in life sciences reflecting the living legacy of the DNA double helix. Topics presented and discussed in the symposium included DNA sequencing, gene editing, central dogma, DNA and immunology, epigenetics, genomics, genomic medicine and genomic neurobiology and technology.
Session III: Central Dogma
1.Presentation by Sunney Xie
The Central Dogma Choreography: Regulation of Gene Modules via Transcription Factor Combinations
Professor Xie shared his group’s insights on using single-molecule microscopy to study the central dogma of molecular biology, in particular gene regulation by transcription factors in human cells. In prokaryotic cells, one transcription factor controls the expression of several genes carrying out a particular biological function together. However, in human cells, each gene encodes for one protein, and is controlled by a combination of transcription factors. Several or tens of proteins within a correlated gene module interact with each other to carry out a particular biological function. Using Tn5 transposase, Professor Xie's group determined the three-dimensional structure of a single human cell for the first time in 2018. They recently found that expressed genes in a correlated gene module are not clustered together in the euchromatin space in a nucleus, but rather regulated and synchronized by shared transcription factors. They recently discovered a double-stranded DNA deaminase, which can convert cytosine to uracil, followed by conversion from uracil to thymine after PCR amplification. As such, they were able to map the genome-wide binding motifs of transcription factors on DNA via FOOt-printing by DeamInasE (FOODIE). This method can measure not only transcription factors’ binding fractions but also their cooperativity in open chromatin regions, and will advance our understanding of eukaryotic gene regulation.
2.Presentation by Yanhui Xu
Structural Insights into Transcription Initiation
Professor Xu talked about efforts on mammalian transcriptional initiation mechanisms. The structures of the transcription pre-initiation complex (PIC), including TFIID, were determined by cryo-EM. The structures revealed the recognition of various types of promoters and the assembly process of complete PIC and proved the role of Mediator in PIC assembly and CTD phosphorylation. Transcription initiation process was visualized by structures of 16 de novo transcribing complexes, showing molecular mechanism of a transition from initially transcribing complex (ITC) to early elongation complex (EEC) accompanying considerable conformational changes. In addition, the mechanism of PIC assembly on chromatin was also studied. Direct interactions between the transcription initiation complex and the +1 nucleosome were found for the first time, indicating that the +1 nucleosome plays an important regulatory role in PIC-Mediator assembly on chromatin. This study established a direct correlation between epigenetic and transcription initiation. The above series of studies provided a framework for the subsequent study of gene expression regulation.
3.Presentation by Hisao Masai
Transcription can Drive DNA Replication
Professor Masai presented discoveries on a novel mode of DNA replication driven by transcription. The study showed that transcription alone can induce replication, shedding light on the DNA replication process in the early stages of evolution. In E. Coli, there exists a transcription-dependent type of replication that occurs mainly in the absence of ribonuclease H, strongly suggesting a role of the RNA-DNA hybrid for this mode of replication. It was also found that G-rich G-quadruplex (G4)-forming sequences could play a key role in the initiation by facilitating the formation of RNA-DNA hybrid., Based on this conjecture, the Masai lab constructed a synthetic replicon, composed of a promoter and a G-rich DNA sequence, which was found to replicate independently as an episome in E. Coli cells. Furthermorr, the entire E. Coli, chromosome was replicated by transcription of a G-rich G4-forming sequences at one location. The results suggest a possibility that the novel transcription-induced replication may also be operative in other species including eukaryotic cells.
4.Presentation by Xiangdong Fu
RNA: Beyond a Message from DNA to Protein
Professor Fu first reviewed the classification and function of RNAs, especially the mechanism of long non-coding RNAs (lncRNAs), and their role in gene transcription regulation, followed by RNA research in the Fu lab. He recalled the development of the genome-wide RNA-chromatin interaction sequencing technology GRID-seq, which facilitated the subsequent research on RNA function. Professor Fu took PVT1 as an example to illustrate how PVT1, as a lncRNA gene, was oncogenic at the RNA level but anti-oncogenic at the DNA level. With the help of Hi-C and GRID-seq technologies, the team also analyzed extrachromosomal DNA (ecDNA) and homogeneous staining region (HSR) and found that PVT1 lncRNA could mediate trans-chromosomal interactions. The Fu lab proposed a model, in which ecDNA could activate transcription through trans-acting enhancers.
Session IV: DNA and Immunology
1.Presentation by Fred Alt
The Fundamental Mechanistic Roles of Chromatin Loop Extrusion in Antibody Gene Diversification
Professor Alt described the mechanism of cohesin-mediated chromatin loop extrusion in antibody gene diversification. In pro-B cells, RAG endonuclease mediates recombination of V, D and J fragments to form variable region exons in the Igh locus. During IgH rearrangements, cohesin is anchored at the recombination center and extrudes DNA through the cohesin ring, allowing the D and VH segments to enter the recombination center where the RAG enzyme mediates rearrangement of D-to-JH first and then VH-to-DJH. During Igκ light chain rearrangement in pre-B cells, loop extrusion also brings Vκ and Jκ segments close to each other, but it was predominantly the strong recombination signal sequences (RSSs) associated with Vκs and Jκs that mediates diffusional rearrangement. This study enriched the knowledge of epigenetics in antibody rearrangement.
2.Presentation by Tak Wah Mak
Neuro-immune Modulations in Health and Diseases
Professor Mak described the impact of metabolism and neuro-immune modulations on tumorigenesis and cancer therapy. Many isocitrate dehydrogenase (IDH) mutations have been identified in multiple tumor types. The mutations create an “oncometabolite” 2-hyroxyglutarate. This metabolite can modify cellular metabolism and epigenetics. Based on previous studies and hypotheses, Mak's team discovered that acetylcholine is produced by T cells and can influence infections, autoimmune diseases and cancer development, suggesting that immunity and neuronal signals may be linked physiologically. These findings emphasize the importance of metabolism and neurotransmission in governing immunity and physiology.
3.Presentation by Zhijian “James” Chen
The Dark Side of DNA - How the Immune System Senses DNA as a Danger Signal
Professor Chen briefly introduced the discovery of cGAS, an intracellular DNA receptor, and the signal transduction of the cGAS-STING pathway. Abnormalities in this pathway may lead to autoimmune diseases, such as Aicardi-Goutières Syndrome (AGS), which is associated with mutations in the DNA exonuclease Trex1. Chen's team confirmed the hypothesis in a Trex1-deficient mouse model, suggesting that cGAS is a therapeutic target for AGS and possibly other autoimmune diseases. The Chen lab also revealed the immune mechanism of bacteria against phage infection by analyzing cGAS-like proteins in prokaryotes.
4.Presentation by Feng Shao
Pyroptosis: From Antibacterial Immunity to Antitumor Immunity
Professor Shao reviewed the discovery of pyroptosis and a key molecule in the pathway, Gasdermin-D. Bacterial lipopolysaccharide (LPS) regulated the non-canonical inflammasome/pyroptosis in antibacterial defense and sepsis. LPS also modulated IL-18 activation through Caspase-4 rather than Caspase-11. Caspase-4/pro-IL18 complex crystal structure revealed a recognition mechanism resembling the recognition of GSDMD. The mechanism of pyroptosis also suggested a potential therapy in antitumor immunity by inducing pyroptosis of tumor cells.
5.Presentation by Robert Langer
From Nanotechnology to mRNA Vaccines
Professor Langer discussed how he applied his chemical engineering background to addressing basic and applied issues in the life sciences,starting with his postdoctoral research with Judah folkman where they isolated the first angiogenesis inhibitors. Critical to this was developing biocompatible nanoparticle and microparticles that could deliver large molecular weight molecules- which the angiogenesis inhibitors were. Prior to Langers work ,delivery of such molecules from tiny particles over a period of time was considered impossible. Langer extended his delivery invention by modifying the surface structure of these particles so as to reduce phagocytosis. These discoveries in angiogenesis inhibition helped lead to the numerous angiogenesis inhibitors used clinically today and the delivery systems led to many clinical products where delivery of macromolecules is crucial for clinical success including mRNA vaccines.
Live Sand Painting Performance of DNA Double Helix 70
