On Apr. 30th 2015, Science published online a breakthrough about mechanisms underlying stem cell aging, which is accomplished by the collaborative team led by Prof. Fuchou Tang (BIOPIC, Peking University), Prof. Guanghui Liu (Institute of Biophysics, Chinese Academy of Sciences) and Prof. Juan Carlos Izpisua Belmonte (Salk Institute). Combining directed differentiation of pluripotent stem cells, gene editing, and epigenomic analysis, this work for the first time established high-order disorganization of heterochromatin as a driving force for human stem cell aging, which could make it a novel target for future anti-aging strategies.
Currently, countries throughout the world are facing the issue of severe population aging. By 2050 about one third of Chinese population may exceed 60 years old. As aging is the biggest risk of human diseases, basic and translational medicine researches aiming at aging are becoming a central and urgent scientific issue for all human beings. However, as the process of human aging is lengthy and complicated, and different from that of model animals such as mouse, it is quite challenging for human aging associated translational medicine researches. Adult progeria (Werner Syndrome, WS) is a rare autosomal recessive disorder, caused by mutations in the WRN gene, which encodes for a RecQ helicase with both helicase and exonuclease activities. From the second decade of life onwards, patients affected by WS develop pathologies that resemble many aspects of human physiological aging, as well as other symptoms associated with aging. Therefore, it is scientifically meaningful to study adult progeria for unveiling the secret of human physiological aging and preventing aging related disorders.
The researchers first came up with the hypothesis that WS patients may suffer from an accelerated degeneration of the mesenchymal stem cell (MSC) pool. They obtained homozygous WRN mutant human embryonic stem cells (ESCs) by gene editing, and created human MSC lines with the unique characteristics of Werner syndrome. Via genome-wide scanning for histone modification, DNA methylome and transcriptome, researchers found that the WS stem cells showed distinguished degeneration in heterochromatin, which mainly showed as the loss of “H3K9me3 mountains” located near the centromeres or telomeres. Further study indicated that WRN co-localized with the heterochromatin protein SUV39H1 and HP1?in the same complex, which stabilized heterochromatin and nuclear lamin and prevented MSC senescence. The deficiency in WRN led to reduction of chromatin-associated proteins and transcription of centromeric loci satellites, which subsequently caused cellular senescence. Compared to the counterparts from younger people, it was observed that in MSCs isolated from healthy elder people, there exited a decreased level of WRN and disorders of heterochromatic structure. This suggested that heterochromatin degeneration may serve as one of the driving forces for normal cellular aging. At last, results showed that overexpression of HP1?can inhibit the accelerated senescence of WS cells, which provided a potential molecular target for preventing human stem cell aging.
It is widely accepted that senescence is due to accumulated DNA damage (genomic instability) in cells. As one of the important supporting evidence: mutations in the DNA repair protein WRN will lead to human adult progeria. This work for the first time utilized the human WS stem cell model, established the novel role of WRN in stabilizing heterochromatin, illustrated that chromatin disorganization drove cellular aging, and thus proposed that human stem cell aging might be due to the crosstalk between epigenetic changes and genomic instability.
This work was accomplished by Institute of Biophysics (CAS), Peking University, Institute of Zoology (CAS), the 306th Hospital of the PLA, Shenzhen University, and Salk Institute. This work was supported by National Natural Science Foundation of China, National Basic Research Program of China (973 Program), the Strategic Priority Research Program of the Chinese Academy of Sciences and PKU-THU Center for Life Sciences.
Science DOI: 10.1126/science.aaa1356