{"doi":"10.1126/scitranslmed.add4666","title":"Multiplex epigenome editing of <i>MECP2</i> to rescue Rett syndrome neurons","abstract":"Rett syndrome (RTT) is an X-linked neurodevelopmental disorder caused by loss-of-function heterozygous mutations of methyl CpG-binding protein 2 ( MECP2 ) on the X chromosome in young females. Reactivation of the silent wild-type MECP2 allele from the inactive X chromosome (Xi) represents a promising therapeutic opportunity for female patients with RTT. Here, we applied a multiplex epigenome editing approach to reactivate MECP2 from Xi in RTT human embryonic stem cells (hESCs) and derived neurons. Demethylation of the MECP2 promoter by dCas9-Tet1 with target single-guide RNA reactivated MECP2 from Xi in RTT hESCs without detectable off-target effects at the transcriptional level. Neurons derived from methylation-edited RTT hESCs maintained MECP2 reactivation and reversed the smaller soma size and electrophysiological abnormalities, two hallmarks of RTT. In RTT neurons, insulation of the methylation-edited MECP2 locus by dCpf1-CTCF (a catalytically dead Cpf1 fused with CCCTC-binding factor) with target CRISPR RNA enhanced MECP2 reactivation and rescued RTT-related neuronal defects, providing a proof-of-concept study for epigenome editing to treat RTT and potentially other dominant X-linked diseases.","journal":"Science Translational Medicine","year":2023,"id":316673,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":95,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9524,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2023-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":854531,"name":"Xiaonan Guan","orcid":"0000-0002-1307-7520","position":1,"is_corresponding":false},{"id":666609,"name":"Bing Xie","orcid":"0000-0002-7408-6762","position":2,"is_corresponding":false},{"id":242237,"name":"Chuanyun Xu","orcid":"0009-0002-1138-871X","position":3,"is_corresponding":false},{"id":994279,"name":"Jacqueline Niu","orcid":"0000-0002-5289-6633","position":4,"is_corresponding":false},{"id":245804,"name":"Xin Tang","orcid":"0000-0003-2883-2610","position":5,"is_corresponding":false},{"id":226573,"name":"Charles H. Li","orcid":"0000-0001-8091-6112","position":6,"is_corresponding":false},{"id":395048,"name":"Henry M. Colecraft","orcid":"0000-0002-2340-8899","position":7,"is_corresponding":false},{"id":30028,"name":"Rudolf Jaenisch","orcid":"0000-0002-2540-7099","position":8,"is_corresponding":false},{"id":245806,"name":"X. Shawn Liu","orcid":"0000-0002-2799-2519","position":9,"is_corresponding":false},{"id":994278,"name":"Junming Qian","orcid":"0000-0002-0453-489X","position":0,"is_corresponding":true}],"reference_count":53,"raw_metadata":null,"created_at":"2026-07-19T01:06:44.698773Z","pmid":"36652535","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}