T+49 (0)30 450540501 (Translational design, muscle stem cells). One sentence summary: Patient primary muscle stems cells gene repaired with >90% efficiency by base editing maintain their regenerative properties for autologous cell replacement therapies of muscular dystrophy.
Whether extension of lifespan provides an extended time without health deteriorations is an important issue for human aging. However, to which degree lifespan and aspects of healthspan regulation might be linked is not well understood. Chromatin factors could be involved in linking both aging aspects, as epigenetic mechanisms bridge regulation of different biological processes. The epigenetic factor LIN-53 (RBBP4/7) associates with different chromatin-regulating complexes to safeguard cell identities in Caenorhabditis elegans as well as mammals, and has a role in preventing memory loss and premature aging in humans. We show that LIN-53 interacts with the nucleosome remodeling and deacetylase (NuRD) complex in C. elegans muscles to ensure functional muscles during postembryonic development and in adults. While mutants for other NuRD members show a normal lifespan, animals lacking LIN-53 die early because LIN-53 depletion affects also the histone deacetylase complex Sin3, which is required for a normal lifespan. To determine why lin-53 and sin-3 mutants die early, we performed transcriptome and metabolomic analysis revealing that levels of the disaccharide trehalose are significantly decreased in both mutants. As trehalose is required for normal lifespan in C. elegans, lin-53 and sin-3 mutants could be rescued by either feeding with trehalose or increasing trehalose levels via the insulin/IGF1 signaling pathway. Overall, our findings suggest that LIN-53 is required for maintaining lifespan and muscle integrity through discrete chromatin regulatory mechanisms.Since both LIN-53 and its mammalian homologs safeguard cell identities, it is conceivable that its implication in lifespan regulation is also evolutionarily conserved. K E Y W O R D Saging, Caenorhabditis elegans, chromatin, epigenetics, healthspan, metabolome S U PP O RTI N G I N FO R M ATI O NAdditional supporting information may be found online in the Supporting Information section at the end of the article. How to cite this article: Müthel S, Uyar B, He M, et al. The conserved histone chaperone LIN-53 is required for normal lifespan and maintenance of muscle integrity in Caenorhabditis elegans. Aging Cell. 2019;18:e13012. https ://doi.
59Whether extension of lifespan provides an extended time without health deteriorations is an 60 important issue for human aging. However, to which degree lifespan and healthspan 61 regulation might be linked is not well understood. Chromatin factors could be involved in 62 linking both aging aspects, as epigenetic mechanisms bridge regulation of different biological 63 processes. The epigenetic factor LIN-53 (RBBP4/7) is required for safeguarding cell 64 identities in Caenorhabditis elegans as well as mammals and for preventing memory loss 65 and premature aging in humans. LIN-53 is a histone chaperone that associates with different 66 chromatin-regulating complexes. We show that LIN-53 interacts with the Nucleosome 67 remodeling and deacteylase (NuRD)-complex in C. elegans muscles to promote healthy 68 locomotion during aging. While mutants for other NuRD members show a normal lifespan, 69 animals lacking LIN-53 die early because LIN-53 depletion affects also the Histone 70 deacetylase complex Sin3, which is required for a normal lifespan. To determine why lin-53 71 and sin-3 mutants die early, we performed transcriptome and metabolome analysis and 72 found that levels of the disaccharide Trehalose are significantly decreased in both mutants. 73As Trehalose is required for normal lifespan in C. elegans, lin-53 and sin-3 mutants could be 74 rescued by either feeding with Trehalose or increasing Trehalose levels via the Insulin/IGF1 75 signaling pathway. Overall, our findings suggest that LIN-53 is required for maintaining 76 lifespan and promoting healthspan through discrete chromatin regulatory mechanisms. Since 77 both LIN-53 and its mammalian homologs safeguard cell identities, it is conceivable that its 78 implication in lifespan and healthspan regulation is also evolutionarily conserved. 79 80 extend the healthspan, meaning the time of life without unfavorable health conditions. 87
LMNA-related muscular dystrophy is an autosomal-dominant progressive disorder caused by mutations in LMNA. LMNA missense mutations are becoming correctable with CRISPR/Cas9-derived tools. Evaluating the functional recovery of LMNA after gene editing bears challenges as there is no reported direct loss of function of lamin A/C proteins in patient-derived cells. The proteins encoded by LMNA are lamins A/C, important ubiquitous nuclear envelope proteins but absent in pluripotent stem cells. We induced lamin A/C expression in induced pluripotent stem cells (iPSCs) of two patients with LMNA-related muscular dystrophy, NM_170707.4 (LMNA): c.1366A > G, p.(Asn456Asp) and c.1494G > T, p.(Trp498Cys), using a short three-day, serum-induced differentiation protocol and analyzed expression profiles of co-regulated genes, examples being COL1A2 and S100A6. We then performed precise gene editing of LMNA c.1366A > G using the near-PAMless (PAM: protospacer-adjacent motif) cytosine base editor. We show that the mutation can be repaired to 100% efficiency in individual iPSC clones. The fast differentiation protocol provided a functional readout and demonstrated increased lamin A/C expression as well as normalized expression of co-regulated genes. Collectively, our findings demonstrate the power of CRISPR/Cas9-mediated gene correction and effective outcome measures in a disease with, so far, little perspective on therapies.
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