**Abstract:** On May 16, 2023, a research team led by Professor Yang Maojun from the School of Life Sciences at Tsinghua University published a significant academic paper in the journal *Genes & Development*. The paper, titled "Hat2p recognizes histone H3 tail to specify the acetylation of newly-synthesized H3/H4 heterodimer by Hat1p/Hat2p complex," elucidates the molecular mechanism by which the Hat1p/Hat2p complex identifies and acetylates newly synthesized H3 and H4 histone heterodimers. **Key Events and Findings:** 1. **Publication and Collaboration:** - The study was a collaborative effort involving Professor Yang Maojun's laboratory, Professor Chai Jijie's laboratory at Tsinghua University, Professor Xu Ruiming's laboratory at the Institute of Biophysics, Chinese Academy of Sciences, and Professor Mark R. Parthun's laboratory at the Ohio State University College of Medicine. - Additional support was provided by Professor Li Haitao from the School of Medicine at Tsinghua University, Dr. Fan Shilong from the Phoenix Project, and the BL17U1 beamline station at the Shanghai Synchrotron Radiation Facility (SSRF). 2. **Background and Significance:** - In eukaryotic cells, chromatin, the fundamental structural unit of chromosomes, is composed of DNA and histone proteins. - Post-translational modifications (PTMs) of histones, such as methylation, acetylation, ubiquitination, and phosphorylation, play crucial roles in regulating chromatin structure and function, influencing processes like transcription, replication, and DNA repair. - Histone acetyltransferases (HATs) are key enzymes that determine and maintain the acetylation levels of histones, which are essential for these processes. - The Hat1p/Hat2p complex is known to acetylate newly synthesized histone H4 before it is incorporated into chromatin. However, the specific mechanism by which this complex recognizes and acetylates the H3/H4 heterodimer was previously unknown. 3. **Molecular Mechanism:** - The researchers used X-ray crystallography to determine the high-resolution structures of the Hat1p/Hat2p/H47-46 complex and the Hat1p/Hat2p/H31-12/H47-46 complex (Figure A). - These structures revealed that Hat2p enhances the acetylation activity of Hat1p by promoting the recognition of the H3 histone tail. Specifically, Hat2p interacts with the unmodified H3R2 residue, which is critical for the specificity of the acetylation process (Figure B). - The team also employed biochemical techniques, such as pull-down assays, to identify key interaction sites between Hat1p and Hat2p. Isothermal titration calorimetry (ITC) was used to further investigate the molecular interactions, showing that Hat2p can recognize differentially modified H3 peptides, potentially modulating histone modifications (Figures C and D). 4. **Evolutionary Insights:** - The study found that the region of Hat1p protein responsible for interacting with Hat2p is not conserved across different species, suggesting that the regulation of this interaction has evolved from simple to complex mechanisms. - In higher organisms, other proteins may be involved in modulating the interaction between Hat1p and Hat2p, adding another layer of complexity to the regulation of histone acetylation. 5. **Novel Binding Mode:** - The researchers discovered that the H3/H4 heterodimer binds to the Hat1p/Hat2p complex in a novel manner (Figure E). This binding mode provides new insights into how histone modifications influence chromatin assembly and histone transport. - The study also highlights the importance of lysine 122 ubiquitination on histone H3, which plays a critical role in the assembly and transport of newly synthesized H3/H4 heterodimers. **Conclusion:** This study by Professor Yang Maojun and his collaborators significantly advances the understanding of the molecular mechanisms governing histone acetylation by the Hat1p/Hat2p complex. The findings not only elucidate the specific interactions between Hat2p and the H3 histone tail but also provide evolutionary and functional insights into the regulation of this process. The novel binding mode of the H3/H4 heterodimer to the Hat1p/Hat2p complex offers a fresh perspective on the role of histone modifications in chromatin dynamics, which is crucial for various cellular processes. **Support and Funding:** - The research was supported by the National Natural Science Foundation of China, the Major Research Plan of the Ministry of Science and Technology, and the Tsinghua-Peking Center for Life Sciences. This abstract summarizes the core events, findings, and implications of the research article, providing a clear and concise overview of the study's significance in the field of molecular biology and chromatin dynamics.