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Scholars have revealed that changes in chromatin structure are the driving force behind human cell aging


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Abnormal activation of early developmental genes caused by large-scale epigenome remodeling is the driving force behind human stem cell aging. Courtesy of the author of the paper

On May 24, The research group of Liu Guanghui, a researcher at the Institute of Zoology of the Chinese Academy of Sciences, and the research group of Qu Jing, a researcher, cooperated with the research group of Zhang Weiqi, a researcher at the Beijing Institute of Genomics of the Chinese Academy of Sciences, and published a research paper online in the journal “Developmental Cells”. By deeply analyzing the epigenome map of human stem cell aging, the study decoded the laws of epigenome remodeling at different levels during aging, and found that the “entropy increase” of chromatin and the abnormal expression of placenta-related genes are the key drivers and molecular markers of cell aging.

Based on the human stem cell aging research system created by the team, the study draws a cross-scale, multi-level and high-resolution epigenome map in the aging process of human stem cells, and deeply analyzes the dynamic changes of nuclear membrane and chromatin interaction during the aging process of human mesenchymal stem cells, the large-scale rearrangement of the radial distribution of chromatin in the nucleus, the reshaping of the advanced structure of chromatin, the transformation of fine chromatin status, and the interaction of different levels of epigenomic information.

It was found that the epigenome of senescent cells showed the loss and increase of chromatin “rigidity”, the increase of epigenome “entropy” and confusion, the weakening of “compartmentalization” characteristics, the convergence of whole genome epigenetic signals and the decrease of “polarity” (loss of epigenetic features of activated genomic regions and inhibitory genomic regions). The researchers defined this phenomenon as “convergent alteration of the epigenetic landscape in aging,” or “Convergent Alteration of the Epigenomic landscape during Aging” (CAEA), and for the first time proposed that the epithetical “seal” release and ectopic expression of placenta, early developmental genes, and lineage-non-essential genes are the drivers and molecular markers of human cell aging.

Liu Guanghui introduced that through the in-depth analysis and integration of the remodeling rules of the epigenome at different levels, the study revealed three core characteristics of epigenetic changes in the aging process of human stem cells:

(1) For the inhibitory genomic region, the loss of the nuclear “rigid framework” (nuclear filament structure) is associated with the “corrosion” of heterochromatin, weakened heterochromatin and nuclear membrane interaction, heterochromatin relaxation, decreased constitutive heterochromatin modification, decreased DNA methylation levels, and increased chromatin accessibility.

(2) For the activated genomic region, it is manifested as the loss of activated characteristics, including: reduced activation histone modification, decreased intensity of chromatin ring interaction and decreased chromatin accessibility.

(3) For the boundary of activated and inhibitory genomic regions, the characteristic chromatin compartment “flipping” and “corrosion” occur, which are manifested as: the switching of activated and inhibitory compartments, the loss of facultative heterochromatin signals, and the loss of the isolation “barrier” of constitutive heterochromatin and facultative heterochromatin and mutual invasion occur more easily at the boundary.

In addition, the study also established a link between genomic structural changes and transcriptional expression disorders in senescent cells, and found that the reduction in epigenomic “characteristic” maintenance of senescent cells is closely related to the transcriptional dysregulation associated with aging. Yao Hongjie, a researcher at the Guangzhou Institute of Biomedicine and Health of the Chinese Academy of Sciences, said, “This discovery not only systematically reveals the correlation and regulation of multidimensional epigenetic information in the aging process of human mesenchymal stem cells, but also provides an important basis for future intervention in aging from the perspective of epigenetic regulation.” ”

Chen Song, a researcher at the Sanger Institute of the Wellcome Foundation in the United Kingdom, said that the study has opened up new ideas for the early diagnosis and prevention of aging and related diseases, and provides a theoretical basis for future design strategies to delay or even reverse aging. (Source: China Science Daily Liu Runan)

Related paper information:https://doi.org/10.1016/j.devcel.2022.05.004



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