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Hutchinson-Gilford progeria syndrome (HGPS or progeria) is typically caused by a dominant-negative C*G-to-T*A mutation (c.1824 C>T; p.G608G) in LMNA, the gene that encodes nuclear lamin A. This mutation causes RNA mis-splicing that produces progerin, a toxic protein that induces rapid ageing and shortens the lifespan of children with progeria to approximately 14 years.sup.1-4. Adenine base editors (ABEs) convert targeted A*T base pairs to G*C base pairs with minimal by-products and without requiring double-strand DNA breaks or donor DNA templates.sup.5,6. Here we describe the use of an ABE to directly correct the pathogenic HGPS mutation in cultured fibroblasts derived from children with progeria and in a mouse model of HGPS. Lentiviral delivery of the ABE to fibroblasts from children with HGPS resulted in 87-91% correction of the pathogenic allele, mitigation of RNA mis-splicing, reduced levels of progerin and correction of nuclear abnormalities. Unbiased off-target DNA and RNA editing analysis did not detect off-target editing in treated patient-derived fibroblasts. In transgenic mice that are 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 (around 20-60% across various organs six months after injection), restoration of normal RNA splicing and reduction of progerin protein levels. In vivo base editing rescued the vascular pathology of the mice, preserving vascular smooth muscle cell counts and preventing adventitial fibrosis. A single injection of ABE-expressing AAV9 at postnatal day 14 improved vitality and greatly extended the median lifespan of the mice from 215 to 510 days. These findings demonstrate the potential of in vivo base editing as a possible treatment for HGPS and other genetic diseases by directly correcting their root cause. In a mouse model of progeria, an adenine base editor delivered with adeno-associated virus corrects the pathogenic mutation in LMNA, rescues vascular pathology and markedly extends the lifespan of the mice., Author(s): Luke W. Koblan [sup.1] [sup.2] [sup.3] , Michael R. Erdos [sup.4] , Christopher Wilson [sup.1] [sup.2] [sup.3] , Wayne A. Cabral [sup.4] , Jonathan M. Levy [sup.1] [sup.2] [sup.3] [...]

Body fat distribution is a heritable trait and a well-established predictor of adverse metabolic outcomes, independent of overall adiposity. To increase our understanding of the genetic basis of body fat distribution and its molecular links to cardiometabolic traits, here we conduct genome-wide association meta-analyses of traits related to waist and hip circumferences in up to 224,459 individuals. We identify 49 loci (33 new) associated with waist-to-hip ratio adjusted for body mass index (BMI), and an additional 19 loci newly associated with related waist and hip circumference measures (P

A study of the super-enhancer landscape in three mouse T-helper lymphocyte subsets identifies nodes that have key roles in cell identity, with the locus encoding Bach2, a key negative regulator of effector differentiation, emerging as the most prominent T-cell super-enhancer. Super-enhancer interaction with T cells Super-enhancers are a group of transcriptional factors specialized for the regulation of cellular functions related to cell identity and genetic disease risk. This study of the super-enhancer landscape in three mouse T-helper lymphocyte subsets identifies nodes that have crucial roles in cell identity, with the Bach2 locus, encoding the transcription factor BACH2, which is an important negative regulator of effector differentiation, emerging as the most prominent T-cell super-enhancer. Perturbation of Bach2 leads to a preferential effect on the expression of super-enhancer-associated genes and non-coding RNAs. This work demonstrates a systematic approach by which the super-enhancer map of relevant cell types can be integrated with human genetics to discover drug target genes. Enhancers regulate spatiotemporal gene expression and impart cell-specific transcriptional outputs that drive cell identity.sup.1. Super-enhancers (SEs), also known as stretch-enhancers, are a subset of enhancers especially important for genes associated with cell identity and genetic risk of disease.sup.2,3,4,5,6. CD4.sup.+ T cells are critical for host defence and autoimmunity. Here we analysed maps of mouse T-cell SEs as a non-biased means of identifying key regulatory nodes involved in cell specification. We found that cytokines and cytokine receptors were the dominant class of genes exhibiting SE architecture in T cells. Nonetheless, the locus encoding Bach2, a key negative regulator of effector differentiation, emerged as the most prominent T-cell SE, revealing a network in which SE-associated genes critical for T-cell biology are repressed by BACH2. Disease-associated single-nucleotide polymorphisms for immune-mediated disorders, including rheumatoid arthritis, were highly enriched for T-cell SEs versus typical enhancers or SEs in other cell lineages.sup.7. Intriguingly, treatment of T cells with the Janus kinase (JAK) inhibitor tofacitinib disproportionately altered the expression of rheumatoid arthritis risk genes with SE structures. Together, these results indicate that genes with SE architecture in T cells encompass a variety of cytokines and cytokine receptors but are controlled by a 'guardian' transcription factor, itself endowed with an SE. Thus, enumeration of SEs allows the unbiased determination of key regulatory nodes in T cells, which are preferentially modulated by pharmacological intervention., Author(s): Golnaz Vahedi [sup.1] , Yuka Kanno [sup.1] , Yasuko Furumoto [sup.2] , Kan Jiang [sup.1] , Stephen C. J. Parker [sup.3] [sup.7] , Michael R. Erdos [sup.3] , Sean [...]

Author(s): Maria Eriksson [1]; W. Ted Brown [2]; Leslie B. Gordon [3]; Michael W. Glynn [4]; Joel Singer [5]; Laura Scott [5]; Michael R. Erdos [1]; Christiane M. Robbins [1]; [...]