Expanding the mecp2 network using comparative genomics reveals potential therapeutic targets for rett syndrome

Irene Unterman, Idit Bloch, Simona Cazacu, Gila Kazimirsky, Bruria Ben-Zeev, Benjamin P. Berman*, Chaya Brodie*, Yuval Tabach*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

8 Scopus citations

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-kB) 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.

Original languageAmerican English
Article numbere67085
JournaleLife
Volume10
DOIs
StatePublished - 6 Aug 2021

Bibliographical note

Publisher Copyright:
© Unterman et al.

Fingerprint

Dive into the research topics of 'Expanding the mecp2 network using comparative genomics reveals potential therapeutic targets for rett syndrome'. Together they form a unique fingerprint.

Cite this