Article
Clinical Neurology
Sarah E. Sinnett, Emily Boyle, Christopher Lyons, Steven J. Gray
Summary: The study shows that controlling the overexpression of MECP2 remains a critical obstacle in gene therapy for Rett syndrome. By developing a risk-driven viral genome design strategy and inserting miRARE into the miniMECP2 gene expression cassette, the safety of gene transfer was greatly improved without compromising efficacy, suggesting a potential use in gene therapy for other dose-sensitive genes.
Article
Medicine, Research & Experimental
Linda Scaramuzza, Giuseppina De Rocco, Genni Desiato, Clementina Cobolli Gigli, Martina Chiacchiaretta, Filippo Mirabella, Davide Pozzi, Marco De Simone, Paola Conforti, Massimiliano Pagani, Fabio Benfenati, Fabrizia Cesca, Francesco Bedogni, Nicoletta Landsberger
Summary: MECP2 mutations cause Rett syndrome, affecting females and altering early brain development. Increasing neuronal activity may delay specific RTT phenotypes.
EMBO MOLECULAR MEDICINE
(2021)
Article
Cell & Tissue Engineering
Ya-Jie Xu, Pei-Pei Liu, Zhong-Ze Yan, Ting-Wei Mi, Ying-Ying Wang, Qian Li, Zhao-Qian Teng, Chang-Mei Liu
Summary: The study revealed that MECP2 deletion led to reduced neuron numbers and simplified dendritic morphology, while treatment with small molecules KW-2449 and VPA, which activate the PI3K-AKT signaling pathway, could alleviate neuronal deficits in RTT models. These findings suggest that KW-2449 and VPA may be promising drugs for the treatment of Rett syndrome.
STEM CELL RESEARCH & THERAPY
(2022)
Article
Biochemistry & Molecular Biology
Qihang Wang, Song Luo, Danyang Xiong, Xiaole Xu, Xiaoyu Zhao, Lili Duan
Summary: DNA methylation is an important epigenetic marker that has gained attention due to three oxidative modifications (hmC, fC, and caC). Mutations in the MBD of MeCP2 result in Rett syndrome, but the effects of DNA modification and MBD mutations on interaction changes remain uncertain. Molecular dynamics simulations were used to investigate the underlying mechanisms, revealing that MBD has the strongest binding ability for mCDNA. The study emphasizes the necessity for targeted Rett compounds that enhance the stability and strength of MBD-DNA interactions.
INTERNATIONAL JOURNAL OF BIOLOGICAL MACROMOLECULES
(2023)
Article
Biochemistry & Molecular Biology
Giuseppe Pepe, Salvatore Fioriniello, Federico Marracino, Luca Capocci, Vittorio Maglione, Maurizio D'Esposito, Alba Di Pardo, Floriana Della Ragione
Summary: Rett syndrome is a severe neurodevelopmental disorder caused by pathogenetic variants in the MECP2 gene. This study found that Rett syndrome patients have impaired brain vascular homeostasis and blood-brain barrier breakdown, which may contribute to the cognitive impairment. The study provides evidence of impaired blood-brain barrier integrity in Rett syndrome and offers new perspectives for novel therapeutic strategies.
Article
Genetics & Heredity
Eugene J. Gardner, Alejandro Sifrim, Sarah J. Lindsay, Elena Prigmore, Diana Rajan, Petr Danecek, Giuseppe Gallone, Ruth Y. Eberhardt, Hilary C. Martin, Caroline F. Wright, David R. FitzPatrick, Helen Firth, Matthew E. Hurles
Summary: Structural variations (SVs) are genetic alterations larger than 50 bp that can lead to genetic diseases, and are often missed by conventional diagnostic methods. By using the InDelible tool, researchers were able to identify rare damaging variants in genes associated with developmental disorders, improving diagnostic yield and potentially expanding understanding of genetic diseases.
AMERICAN JOURNAL OF HUMAN GENETICS
(2021)
Article
Endocrinology & Metabolism
Ana P. M. Canton, Flavia R. Tinano, Leonardo Guasti, Luciana R. Montenegro, Fiona Ryan, Deborah Shears, Maria Edna de Melo, Larissa G. Gomes, Mariana P. Piana, Raja Brauner, Rafael Espino-Aguilar, Arancha Escribano-Munoz, Alyssa Paganoni, Jordan E. Read, Marta Korbonits, Carlos E. Seraphim, Silvia S. Costa, Ana Cristina Krepischi, Alexander A. L. Jorge, Alessia David, Lena R. Kaisinger, Ken K. Ong, John R. B. Perry, Ana Paula Abreu, Ursula B. Kaiser, Jesus Argente, Berenice B. Mendonca, Vinicius N. Brito, Sasha R. Howard, Ana Claudia Latronico
Summary: This study aimed to investigate the association between MECP2 variants and idiopathic central precocious puberty. The results showed that a small number of girls carried rare MECP2 gene variants, resulting in central precocious puberty, but without severe neurodevelopmental abnormalities. This finding suggests the involvement of MECP2 in the hypothalamic control of human pubertal timing and provides evidence for the role of epigenetic and genetic mechanisms in this crucial biological process.
LANCET DIABETES & ENDOCRINOLOGY
(2023)
Article
Biology
Erik Waskiewicz, Michalis Vasiliou, Isaac Corcoles-Saez, Rita S. Cha
Summary: Through data mining and functional genetic analysis, the study identified functionally important and evolutionarily conserved residues in ATM/ATR, shedding light on their diverse roles in enzyme functions. The findings suggest that loss of intrinsic kinase activity in ATM/ATR is infrequent in carcinogenesis.
COMMUNICATIONS BIOLOGY
(2021)
Review
Genetics & Heredity
Osman Sharifi, Dag H. Yasui
Summary: The MeCP2 protein, encoded by the MECP2 gene, plays a key role in DNA binding and transcription, particularly in relation to Rett syndrome. Despite uncertainties about its full range of functions, research on MeCP2 mainly relies on cell and animal models. Studies discussed various aspects of MeCP2 and Rett syndrome, explored conflicting evidence in emerging areas, identified gaps in research, and examined the latest discoveries focusing on potential treatments and therapies.
FRONTIERS IN GENETICS
(2021)
Article
Biochemistry & Molecular Biology
Jiao Wang, Yushuo Xiao, Chengyu Liu, Yixue Huang, Robert B. Petersen, Ling Zheng, Kun Huang
Summary: MeCP2 plays a crucial role in both neurological and non-neurological disorders, including causing Rett syndrome in the former and cardiac dysfunction, liver injury, respiratory disorders, and other conditions in the latter. Research suggests that MeCP2 can influence various physiological and pathological processes in a DNA methylation-dependent or independent manner.
ARCHIVES OF BIOCHEMISTRY AND BIOPHYSICS
(2021)
Article
Oncology
Jiajia Zhang, Zhenzhen Yan, Yukun Wang, Yaguang Wang, Xin Guo, Ju Jing, Xiangnan Dong, Shasha Dong, Xiuhua Liu, Xiaochun Yu, Chen Wu
Summary: The study examined mutations in the TP53 binding protein 1 (53BP1) gene in various human cancers, revealing that these mutations may disrupt the DNA damage repair function of 53BP1 and impact genomic stability.
Article
Neurosciences
Yasmine Belaidouni, Diabe Diabira, Jinwei Zhang, Jean-Charles Graziano, Francesca Bader, Aurelie Montheil, Clement Menuet, Gary A. Wayman, Jean-Luc Gaiarsa
Summary: The study found that in late symptomatic stages, there was no difference in the relative amount of KCC2 and NKCC1 in the hippocampus of Mecp2-null mice, but there was over-phosphorylation. There were also no differences in the inhibitory strength and reversal potential of GABA(A)-receptor-mediated responses in Mecp2-null CA3 pyramidal neurons compared to wild-type at any stages studied. These data indicate the presence of a functional chloride extrusion mechanism in Mecp2-null CA3 pyramidal neurons at symptomatic stages.
FRONTIERS IN CELLULAR NEUROSCIENCE
(2021)
Review
Genetics & Heredity
Laura FitzPatrick, Adrian Bird
Summary: The review highlights the genetic basis of many neurological disorders and the efforts being made to develop genetic strategies for treating monogenic neurological disorders. It also addresses the challenges and ethical difficulties that may arise in the process.
Article
Multidisciplinary Sciences
Deivid C. Rodrigues, Marat Mufteev, Kyoko E. Yuki, Ashrut Narula, Wei Wei, Alina Piekna, Jiajie Liu, Peter Pasceri, Olivia S. Rissland, Michael D. Wilson, James Ellis
Summary: This study measured transcription rate and mRNA half-life changes in RTT patient-derived neurons and reinterpreted nuclear and whole-cell RNAseq from Mecp2 mice. The results showed that dysregulation of genes in RTT is caused by changes in transcription rate or half-life, but genes are buffered when both change. In addition, three dinucleotide frequencies were found to be better predictors of transcription rate changes than CA and CG. MicroRNA and RNA-binding Protein (RBP) motifs were enriched in the 3'UTRs of genes with half-life changes, while nuclear RBP motifs were enriched in buffered genes with increased transcription rate. The study revealed post-transcriptional mechanisms in neurodevelopmental disorders caused by mutations in transcriptional modulator genes.
NATURE COMMUNICATIONS
(2023)
Review
Oncology
Kazem Nejati-Koshki, Chris-Tiann Roberts, Ghader Babaei, Mojgan Rastegar
Summary: Epigenetic mechanisms control gene expression and cellular identity, with DNA methylation being an important epigenetic modification. Methyl-CpG-Binding Protein 2 (MeCP2) is a reader of DNA methylation and plays key roles in cellular identity and function. Recent studies have uncovered MeCP2's involvement in tumorigenesis of various human cancers, highlighting its potential oncogenic properties. This article provides an overview of the emerging role of MeCP2 as an oncogene in different types of human cancer.
Article
Biochemistry & Molecular Biology
Philipp Rentzsch, Daniela Witten, Gregory M. Cooper, Jay Shendure, Martin Kircher
NUCLEIC ACIDS RESEARCH
(2019)
Article
Genetics & Heredity
Jose L. McFaline-Figueroa, Andrew J. Hill, Xiaojie Qiu, Dana Jackson, Jay Shendure, Cole Trapnell
Article
Biochemical Research Methods
Hannah A. Pliner, Jay Shendure, Cole Trapnell
Article
Biology
Jes Alexander, Gregory M. Findlay, Martin Kircher, Jay Shendure
Review
Genetics & Heredity
Molly Gasperini, Jacob M. Tome, Jay Shendure
NATURE REVIEWS GENETICS
(2020)
Article
Biotechnology & Applied Microbiology
Junyue Cao, Wei Zhou, Frank Steemers, Cole Trapnell, Jay Shendure
NATURE BIOTECHNOLOGY
(2020)
Article
Biochemical Research Methods
Jason C. Klein, Vikram Agarwal, Fumitaka Inoue, Aidan Keith, Beth Martin, Martin Kircher, Nadav Ahituv, Jay Shendure
Article
Multidisciplinary Sciences
He Fang, Giancarlo Bonora, Jordan P. Lewandowski, Jitendra Thakur, Galina N. Filippova, Steven Henikoff, Jay Shendure, Zhijun Duan, John L. Rinn, Xinxian Deng, William S. Noble, Christine M. Disteche
NATURE COMMUNICATIONS
(2020)
Article
Biochemistry & Molecular Biology
Timothy J. Durham, Riza M. Daza, Louis Gevirtzman, Darren A. Cusanovich, Olubusayo Bolonduro, William Stafford Noble, Jay Shendure, Robert H. Waterston
Summary: Recent developments in single-cell technologies have allowed researchers to study cell states in Caenorhabditis elegans at a higher resolution, including gene expression patterns and chromatin accessibility. A novel implementation of the latent Dirichlet allocation algorithm has identified 37 clusters of cells corresponding to different cell types in the worm, providing new insights into cellular differentiation and gene regulation.
Article
Multidisciplinary Sciences
Vikram Agarwal, Sereno Lopez-Darwin, David R. Kelley, Jay Shendure
Summary: This study quantifies the differential usage of 3' UTR isoforms among cell types during mouse embryonic development, showing a global lengthening of 3' UTRs across all cell types with specific RNA-binding proteins (RBPs) regulating this process.
NATURE COMMUNICATIONS
(2021)
Article
Biotechnology & Applied Microbiology
Junhong Choi, Wei Chen, Chase C. Suiter, Choli Lee, Florence M. Chardon, Wei Yang, Anh Leith, Riza M. Daza, Beth Martin, Jay Shendure
Summary: The PRIME-Del method induces deletions with high precision using a pair of prime editing sgRNAs, outperforming CRISPR-Cas9 and sgRNA pairs in programming deletions up to 10 kb. This method can be broadly useful for precise, flexible programming of genomic deletions and potentially other rearrangements.
NATURE BIOTECHNOLOGY
(2022)
Letter
Biochemistry & Molecular Biology
Michael Boeckh, Helen Y. Chu, Janet A. Englund, Christina M. Lockwood, Deborah A. Nickerson, Jay Shendure, Lea Starita
Article
Hematology
Jill M. Johnsen, Shelley N. Fletcher, Angela Dove, Haley McCracken, Beth K. Martin, Martin Kircher, Neil C. Josephson, Jay Shendure, Sarah E. Ruuska, Leonard A. Valentino, Glenn F. Pierce, Crystal Watson, Dunlei Cheng, Michael Recht, Barbara A. Konkle
Summary: The findings of this study report the results of the largest hemophilia genotyping project performed to date. The results support the importance of comprehensive genetic approaches in hemophilia and contribute to a better understanding of variation in the F8 and F9 genes and the risks of inhibitor formation.
JOURNAL OF THROMBOSIS AND HAEMOSTASIS
(2022)
Article
Multidisciplinary Sciences
Bailey A. T. Weatherbee, Carlos W. Gantner, Lisa K. Iwamoto-Stohl, Riza M. Daza, Nobuhiko Hamazaki, Jay Shendure, Magdalena Zernicka-Goetz
Summary: By inducing stem cells, we have established a model of the human post-implantation embryo that mimics key aspects of human development and allows us to study tissue-tissue interactions. This model is important for investigating critical questions related to human post-implantation development and understanding the causes of pregnancy failure during this stage.