This study is led by Dr. Xiaodong Luan (Institute of Clinical Medicine, Peking Union Medical College Hospital), Dr. Shuyang Zhang (Department of Rare Diseases, Peking Union Medical College Hospital) and Dr. He Huang (Shanghai Institute of Materia Medica, Chinese Academy of Sciences). Multi-omics research, including global proteomics, lactylome profiling, and genome-wide RNA sequencing (RNA-seq), to unveil changes that occurr at different molecular levels throughout postnatal heart development. "The significant alterations in proteins, lactylation, and gene expression related to energy and nucleic acid metabolism during the early postpartum stages from 1 to 6 weeks (1 w to 6 w) post-birth and remained stable after 6 weeks." Luan says.
In addition, the team proposed that non-histone lactylation levels accumulate progressively from 1 week to 6 months (6 m), whereas histone lactylation levels decrease rapidly from 1 to 6 weeks postpartum. "This is an interesting finding that the lactylation levels of histones and non-histones vary considerably during heart development." says Luan.
The researchers conducted KEGG pathway analysis of differentially expressed proteins between the 1 w and 6 w mouse heart, revealing that proteins enriched in the TCA cycle and respiratory electron transport pathways were significantly upregulated from 1 w to 6 w. Simultaneously, proteins related to the processing of capped intron-containing pre-mRNA were significantly decreased. Overall, the process involved the down-regulation of transcriptional regulation and up-regulation of energy metabolism.
The team also indicated that more developmental, morphogenetic, and metabolic processes were elevated in the adolescent mouse heart, including cellular response to chemical stimulus, organic acid metabolic processes, generation of precursor metabolites and energy, muscle system processes, developmental regulation, and lipid biosynthetic processes. Conversely, the adolescent mouse heart exhibited a downregulation of nucleic acid metabolism pathways, such as cell cycle, nuclear division, chromosome segregation, and DNA replication. "These results offer valuable insights for biomarker discovery and molecular targeting of the developmental maturation process within the heart." says Luan.
In addition, the researchers identified that histone 4 lysine 12 lactylation (H4K12la) acts as a vital upstream regulatory element in mouse hearts from 1 w to 6 w post-birth. The decreased gene expression levels of Mex3b, Vstm5, Rfc3, and E2f2, as well as the reduced H4K12la enrichment in the promoter regions of these genes in 1 w mouse cardiac tissue compared to 6 w. Mex3b exhibited enhanced expression throughout the three early phases of osteogenic differentiation, Vstm5 has been demonstrated to promote dendritic spines development, Rfc3 can affect the Wnt/β catenin pathway, while E2f2 plays a role in cell cycle regulation as a transcription factor. "Our results conclusively demonstrated that H4K12la plays a role in regulating downstream gene expression in the mouse heart, thereby influencing DNA replication and subsequently impacting the corresponding phenotype of the mouse." says Luan.
In summary, this study has mainly focused on understanding the functional role of non-histone lactylation and Kla during cardiac development, highlighting the potential implications of Kla in cardiac regeneration and aging. Through multi-omics analysis, we have demonstrated the pivotal role of H4K12la in regulating downstream genes. Therefore, histone Kla stands as a regulator of the cardiomyocyte cell cycle during cardiac development, holding promise as a potential target for inducing cardiac regeneration in the clinical setting. "The role of Kla in mediating early cardiac development and provides potential therapeutic strategies and treatment targets for heart disease and repair," says Luan.
See the article:
Epigenetic regulation of cardiac tissue development by lysine lactylation
https://doi.org/10.1016/j.hlife.2024.12.005
Funders: The grants for the paper. National Key Research and Development Program Funding (2023YFC3605504), National High-Level Hospital Clinical Research Funding (2022-PUMCH-B-098), National Natural Science Foundation of China (22277125 and 92253306), Natural Science Foundation of Shanghai (23ZR1474600), Shanghai Municipal Science and Technology Major Project and Tsinghua-Peking Center for Life Sciences (045-61020100123).
