Expanding the MECP2 network using comparative genomics reveals potential therapeutic targets for Rett syndrome
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 networ...
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| Format: | Article |
| Language: | English |
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eLife Sciences Publications Ltd
2021-08-01
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| Series: | eLife |
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| Online Access: | https://elifesciences.org/articles/67085 |
| _version_ | 1811252865097793536 |
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| author | Irene Unterman Idit Bloch Simona Cazacu Gila Kazimirsky Bruria Ben-Zeev Benjamin P Berman Chaya Brodie Yuval Tabach |
| author_facet | Irene Unterman Idit Bloch Simona Cazacu Gila Kazimirsky Bruria Ben-Zeev Benjamin P Berman Chaya Brodie Yuval Tabach |
| author_sort | Irene Unterman |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-04-12T16:41:04Z |
| format | Article |
| id | doaj.art-190ef8124c044965b9e74f2959590c48 |
| institution | Directory Open Access Journal |
| issn | 2050-084X |
| language | English |
| last_indexed | 2024-04-12T16:41:04Z |
| publishDate | 2021-08-01 |
| publisher | eLife Sciences Publications Ltd |
| record_format | Article |
| series | eLife |
| spelling | doaj.art-190ef8124c044965b9e74f2959590c482022-12-22T03:24:45ZengeLife Sciences Publications LtdeLife2050-084X2021-08-011010.7554/eLife.67085Expanding the MECP2 network using comparative genomics reveals potential therapeutic targets for Rett syndromeIrene Unterman0https://orcid.org/0000-0002-5697-9612Idit Bloch1Simona Cazacu2https://orcid.org/0000-0002-6085-4177Gila Kazimirsky3Bruria Ben-Zeev4Benjamin P Berman5https://orcid.org/0000-0002-2099-9005Chaya Brodie6Yuval Tabach7https://orcid.org/0000-0001-9521-3217Department of Developmental Biology and Cancer Research, Institute for Medical Research Israel-Canada, Jerusalem, IsraelDepartment of Developmental Biology and Cancer Research, Institute for Medical Research Israel-Canada, Jerusalem, IsraelHermelin Brain Tumor Center, Henry Ford Hospital, Detroit, United StatesThe Mina and Everard Goodman Faculty of Life Sciences, Bar-Ilan University, Ramat-Gan, IsraelEdmond and Lily Safra Children's Hospital, Chaim Sheba Medical Center, Ramat Gan, IsraelDepartment of Developmental Biology and Cancer Research, Institute for Medical Research Israel-Canada, Jerusalem, IsraelThe Mina and Everard Goodman Faculty of Life Sciences, Bar-Ilan University, Ramat-Gan, IsraelDepartment of Developmental Biology and Cancer Research, Institute for Medical Research Israel-Canada, Jerusalem, IsraelInactivating 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.https://elifesciences.org/articles/67085rett syndromephylogenetic profilingcomparative genomicspacritiniberythropoietindimethyl fumarate |
| spellingShingle | Irene Unterman Idit Bloch Simona Cazacu Gila Kazimirsky Bruria Ben-Zeev Benjamin P Berman Chaya Brodie Yuval Tabach Expanding the MECP2 network using comparative genomics reveals potential therapeutic targets for Rett syndrome eLife rett syndrome phylogenetic profiling comparative genomics pacritinib erythropoietin dimethyl fumarate |
| title | Expanding the MECP2 network using comparative genomics reveals potential therapeutic targets for Rett syndrome |
| title_full | Expanding the MECP2 network using comparative genomics reveals potential therapeutic targets for Rett syndrome |
| title_fullStr | Expanding the MECP2 network using comparative genomics reveals potential therapeutic targets for Rett syndrome |
| title_full_unstemmed | Expanding the MECP2 network using comparative genomics reveals potential therapeutic targets for Rett syndrome |
| title_short | Expanding the MECP2 network using comparative genomics reveals potential therapeutic targets for Rett syndrome |
| title_sort | expanding the mecp2 network using comparative genomics reveals potential therapeutic targets for rett syndrome |
| topic | rett syndrome phylogenetic profiling comparative genomics pacritinib erythropoietin dimethyl fumarate |
| url | https://elifesciences.org/articles/67085 |
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