Summary Hutchinson-Gilford progeria syndrome (HGPS) is typically caused by a dominant-negative C•G-to-T•A mutation (c.1824 C>T, G608G) in LMNA , the nuclear lamin A gene. This mutation causes RNA mis-splicing that produces progerin, a toxic protein that induces rapid aging and shortens lifespan to ~14 years 1 – 4 . Adenine base editors (ABEs) perform targeted A•T-to-G•C base pair conversion with minimal byproducts and without requiring double-strand DNA breaks or donor DNA templates 5 , 6 . Here, we describe the use of an ABE to directly correct the pathogenic HGPS mutation in cultured progeria patient-derived fibroblasts and in a mouse model of HGPS. Lentiviral delivery of ABE to patient-derived fibroblasts results in ~90% correction of the pathogenic allele, mitigation of RNA mis-splicing, reduced progerin levels, and correction of nuclear abnormalities. Unbiased off-target DNA and RNA analysis did not detect off-target editing activity in treated patient-derived fibroblasts. In transgenic mice homozygous for the human LMNA c.1824 C>T allele, a single retro-orbital injection of adeno-associated virus 9 (AAV9) encoding the ABE resulted in substantial, durable correction of the pathogenic mutation (~20-60% across various organs 6 months post-injection), restoration of normal RNA splicing, and reduction of progerin protein. In vivo base editing rescued vascular pathology, preserving vascular smooth muscle cell counts and preventing adventitial fibrosis. A single ABE AAV9 injection at P14 improved animal vitality and greatly extended median lifespan from 215 to 510 days. These findings support the potential of in vivo base editing to treat HGPS, and other genetic diseases, by directly correcting the root cause of disease.

Developmental transitions are guided by master regulatory transcription factors. During adipogenesis, a transcriptional cascade culminates in the expression of PPARγ and C/EBPα, which orchestrate activation of the adipocyte gene expression program. However, the coactivators controlling PPARγ and C/EBPα expression are less well characterized. Here, we show the bromodomaincontaining protein, BRD4, regulates transcription of PPARγ and C/EBPα. Analysis of BRD4 chromatin occupancy reveals that induction of adipogenesis in 3T3L1 fibroblasts provokes dynamic redistribution of BRD4 to de novo super-enhancers proximal to genes controlling adipocyte differentiation. Inhibition of the bromodomain and extraterminal domain (BET) family of bromodomain-containing proteins impedes BRD4 occupancy at these de novo enhancers and disrupts transcription of Pparg and Cebpa, thereby blocking adipogenesis. Furthermore, silencing of these BRD4-occupied distal regulatory elements at the Pparg locus by CRISPRi demonstrates a critical role for these enhancers in the control of Pparg gene expression and adipogenesis in 3T3L1s. Together, these data establish BET bromodomain proteins as time-and context-dependent coactivators of the adipocyte cell state transition.chromatin | coactivator | BET bromodomain | adipogenesis | transcription

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This paper presents the first multi-tissue study of diet in post-medieval London using both the stable light isotope analysis of carbon and nitrogen and analysis of microdebris in dental calculus. Dietary intake was explored over short and long timescales. Bulk bone collagen was analysed from humans from the Queen's Chapel of the Savoy (QCS) (n = 66) and the St Barnabas/St Mary Abbots (SB) (n = 25). Incremental dentine analysis was performed on the second molar of individual QCS1123 to explore childhood dietary intake. Bulk hair samples (n = 4) were sampled from adults from QCS, and dental calculus was analysed from four other individuals using microscopy. In addition, bone collagen from a total of 46 animals from QCS (n = 11) and the additional site of Prescot Street (n = 35) was analysed, providing the first animal dietary baseline for post-medieval London. Overall, isotopic results suggest a largely C 3-based terrestrial diet for both populations, with the exception of QCS1123 who exhibited values consistent with the consumption of C 4 food sources throughout childhood and adulthood. The differences exhibited in δ 15 N coll across both populations likely reflect variations in diet due to social class and occupation, with individuals from SB likely representing wealthier individuals consuming larger quantities of animal and marine fish protein. Microdebris analysis results were limited but indicate the consumption of domestic cereals. This paper demonstrates the utility of a multidisciplinary approach to investigate diet across long and short timescales to further our understanding of variations in social status and mobility.