Science of Fudan University recently published an article: revealing the mechanism of +1 nucleosome regulating transcriptional initiation

As the core of gene expression regulation, the transcriptional initiation process occurs in the promoter region of the gene, exposing the promoter by removing nucleosomes from the chromatin remodeling complex, allowing the assembly of the preinitiation complex (PIC) to assemble into the PIC-Mediator transcriptional initiation supercomplex
with the help of a mediator 。 Xu Yanhui's team published four consecutive Science papers (1-4) in 2020 and 2021, and made a series of important breakthroughs in the research on the starting mechanism of human transcription, and some of the results were selected as the top ten advances
in China's life sciences in 2021.

On October 7, 2022, Xu Yanhui's research group published a research paper
entitled "Structures of +1 nucleosome – bound PIC-Mediator complex" online in the journal Science 。 This study analyzes the structure of the PIC-Mediator complex containing +1 nucleosomes (the first nucleosome downstream of the promoter), shows for the first time the close binding of the transcriptional initiation complex to the +1 nucleosomes, shows the important regulatory role of +1 nucleosomes on the assembly of transcriptional initiation complexes on chromatin (Figure 1), and establishes a direct correlation between
epigenetics and transcriptional initiation.

Figure 1: PIC-Mediator structure with +1 nucleosomes

The research team constructed a template containing nucleosomes and promoters, and successfully assembled the PIC-Mediator transcriptional initiation supercomplex containing +1 nucleosomes (84 proteins, molecular weight 4.
3MD) by using in vitro reconstruction methods, and through structural and biochemical analysis, it was found that there were multiple direct interactions and multiple modes of action between +1 nucleosomes and PIC-Mediator complexes, and by binding multiple subunits of TFIIH and Mediator, Promotes the assembly and transcriptional initiation activity
of PIC-Mediator on chromatin.

At present, the mainstream concept is that the transcription machine will not encounter the nucleosomes until it enters the extension stage, and this work shows for the first time at the molecular level the close binding of the transcriptional initiation complex to the +1 nucleosome, and establishes a direct correlation between
the epigenetic signal near the transcriptional initiation site and transcriptional initiation 。 A series of transcriptional initiation events (RNA synthesis, polymerase forward shift, pause, release, capping, extension, etc.
) occurring within the range of dozens of nucleotides (about 14 nanometers) from the transcriptional initiation site to the +1 nucleosomes (about 14 nanometers), and the dynamic dissociation and binding of dozens of different transcriptional regulatory complexes (hundreds of proteins) all need to consider the influence of +1 nucleosomes and their epigenetic regulation (Figure 2).

This research will change our traditional view of the interrelationship between the transcriptional initiation process and chromatin represented by +1 nucleosomes, and provide a new guiding framework and structural basis
for the study of epigenetics and gene expression regulation.

Figure 2.
+1 nucleosomes may play a role
in the process of extended series movement from transcriptional initiation to early transcription.
From the transcriptional initiation site to the +1 nucleosomes is about 40bp, about 14 nanometers, and a series of early transcriptional events occur in this range, which is also the core region
of gene expression regulation.

Chen Xizi, a young researcher at the School of Life Sciences of Fudan University and a part-time researcher at the Affiliated Cancer Hospital, Wang Xinxin, a 2020 doctoral student at the Institute of Biomedical Sciences, and Liu Weida, a 2019 direct doctoral student, are the co-authors of this paper, and Xu Yanhui, a researcher at the Affiliated Cancer Hospital and a part-time researcher at the Institute of Biomedical Sciences, is the corresponding author
.

Original link: 1.
Chen, X.
, Qi, Y.
, Wu, Z.
, Wang, X.
, Li, J.
, Zhao, D.
, Hou, H.
, Li, Y.
, Yu, Z.
, Liu, W.
, Wang, M.
, Ren, Y.
, Li, Z.
, Yang, H.
, and Xu, Y.
* (2021) Structural insights into preinitiation complex assembly on core promoters.
Science, eaba8490

 2.
Chen, X.
, Yin, X.
, Li, J.
, Wu, Z.
, Qi, Y.
, Wang, X.
, Liu, W.
, and Xu, Y.
*(2021) Structures of the human Mediator and Mediator-bound preinitiation complex.
 Science, eabg0635

 3.
Zheng, H.
, Qi, Y.
, Hu, S.
, Cao, X.
, Xu, C.
, Yin, Z.
, Chen, X.
, Li, Y.
, Liu, W.
, Li, J.
, Wang, J.
, Wei, G.
, Liang, K.
, Chen, F.
X.
*, and Xu, Y.
* (2020) Identification of Integrator-PP2A complex (INTAC), an RNA polymerase II phosphatase.
 Science 370, eabb5872

 4.
He, S.
, Wu, Z.
, Tian, Y.
, Yu, Z.
, Yu, J.
, Wang, X.
, Li, J.
, Liu, B.
, and Xu, Y.
* (2020) Structure of Nucleosome-bound human BAF Complex.
 Science 367: 875-881