Expanding the MECP2 network using comparative genomics reveals potential therapeutic targets for Rett syndrome.

Content Provider	Europe PMC
Author	Unterman, Irene Bloch, Idit Cazacu, Simona Kazimirsky, Gila Ben-Zeev, Bruria Berman, Benjamin P Brodie, Chaya Tabach, Yuval
Editor	Perry, George H
Copyright Year	2021
Abstract	Inactivating mutations in the Methyl-CpG Binding Protein 2 (MECP2) gene are the main cause of Rett syndrome (RTT). Despite extensive research into MECP2 function, no treatments for RTT are currently available. Here, we used an evolutionary genomics approach to construct an unbiased MECP2 gene network, using 1028 eukaryotic genomes to prioritize proteins with strong co-evolutionary signatures with MECP2. Focusing on proteins targeted by FDA-approved drugs led to three promising targets, two of which were previously linked to MECP2 function (IRAK, KEAP1) and one that was not (EPOR). The drugs targeting these three proteins (Pacritinib, DMF, and EPO) were able to rescue different phenotypes of MECP2 inactivation in cultured human neural cell types, and appeared to converge on Nuclear Factor Kappa B (NF-κB) signaling in inflammation. This study highlights the potential of comparative genomics to accelerate drug discovery, and yields potential new avenues for the treatment of RTT.
Journal	eLife
Volume Number	10
PubMed Central reference number	PMC8346285
PubMed reference number	34355696
e-ISSN	2050084X
DOI	10.7554/elife.67085
Language	English
Publisher	eLife Sciences Publications, Ltd
Publisher Date	2021-08-06
Access Restriction	Open
Rights License	This article is distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use and redistribution provided that the original author and source are credited. © 2021, Unterman et al
Subject Keyword	rett syndrome phylogenetic profiling comparative genomics pacritinib erythropoietin dimethyl fumarate Human
Content Type	Text
Resource Type	Article
Subject	Immunology and Microbiology Neuroscience Medicine Biochemistry, Genetics and Molecular Biology