DGCR8 Overexpression Attenuates the Accumulation of Senescent Cells with Age

Given the newfound acceptance of cellular senescence as an important cause of aging, many more research groups are assessing the impact of senescent cells in their research into aging. Here, the focus is on chromatin organization, a collection of nuclear structures and processes in the cell that appear to have some influence over the pace of aging over a lifetime. The researchers discover that the gene DGCR8 accelerates the appearance of senescent cells and dysfunction when mutated, and thus producing broken protein machinery, but slows the accumulation of lingering senescent cells when overexpressed in its correct form. This touches on some of the same machinery of the cell as the mir-122 findings discussed a few days ago, and that work is worth comparing with the notes here, as an example of just how complicated this all is.

Stem cell aging is newly recognized as an important culprit in organismal aging. For example, aging of mesenchymal stem cells (MSCs) has been shown to drive aging-associated tissue degeneration. MSCs, which have the potential to differentiate into mesodermal lineages like osteoblasts, chondrocytes, and adipocytes, can be isolated from various tissues including bone marrow, cord blood, adipose tissue, and dental pulp. Premature depletion of MSCs is observed in patients with Hutchinson-Gilford progeria syndrome (HGPS) and Werner syndrome (WS), two premature aging diseases that are associated with accelerated atherosclerosis, osteoporosis, and osteoarthritis. Despite numerous studies showing that MSCs play pivotal roles in tissue rejuvenation, regeneration, and repair by differentiating into various somatic cell types, little is known about the key regulators of MSC aging.

Aging-associated declines in stem cell functionality are often accompanied by epigenetic changes, such as changes in genomic DNA methylation, histone modifications, and chromatin remodeling enzymes. Heterochromatin domains are structurally inaccessible and usually transcriptionally inactive. These domains are established during early stages of embryogenesis and are gradually lost with aging, resulting in the de-repression of normally silenced genes. Whereas heterochromatin loss drives human MSC (hMSC) aging, the re-establishment of heterochromatin alleviates premature aging and promotes longevity in Drosophila and human cells, suggesting that the maintenance of heterochromatin organization could be an effective therapeutic intervention against aging.

DiGeorge syndrome critical region 8 (DGCR8) is a critical component of the canonical microprocessor complex for microRNA biogenesis. Here, we demonstrate that DGCR8 plays an important role in maintaining heterochromatin organization and attenuating aging. A truncated version of DGCR8 accelerated senescence in human mesenchymal stem cells (hMSCs) independent of its microRNA-processing activity. Further studies revealed that DGCR8 maintained heterochromatin organization. DGCR8 was downregulated in pathologically and naturally aged hMSCs, whereas DGCR8 overexpression alleviated hMSC aging and mouse osteoarthritis. Taken together, these analyses uncovered a novel, microRNA processing-independent role in maintaining heterochromatin organization and attenuating cellular senescence by DGCR8, thus representing a new therapeutic target for alleviating human aging-related disorders.

Link: https://doi.org/10.1038/s41467-019-10831-8

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