Table_4_The Promoter Regions of Intellectual Disability-Associated Genes Are Uniquely Enriched in LTR Sequences of the MER41 Primate-Specific Endogenous Retrovirus: An Evolutionary Connection Between Immunity and Cognition.XLSX
Social behavior and neuronal connectivity in rodents have been shown to be shaped by the prototypical T lymphocyte-derived pro-inflammatory cytokine Interferon-gamma (IFNγ). It has also been demonstrated that STAT1 (Signal Transducer And Activator Of Transcription 1), a transcription factor (TF) crucially involved in the IFNγ pathway, binds consensus sequences that, in humans, are located with a high frequency in the LTRs (Long Terminal Repeats) of the MER41 family of primate-specific HERVs (Human Endogenous Retroviruses). However, the putative role of an IFNγ/STAT1/MER41 pathway in human cognition and/or behavior is still poorly documented. Here, we present evidence that the promoter regions of intellectual disability-associated genes are uniquely enriched in LTR sequences of the MER41 HERVs. This observation is specific to MER41 among more than 130 HERVs examined. Moreover, we have not found such a significant enrichment in the promoter regions of genes that associate with autism spectrum disorder (ASD) or schizophrenia. Interestingly, ID-associated genes exhibit promoter-localized MER41 LTRs that harbor TF binding sites (TFBSs) for not only STAT1 but also other immune TFs such as, in particular, NFKB1 (Nuclear Factor Kappa B Subunit 1) and STAT3 (Signal Transducer And Activator Of Transcription 3). Moreover, IL-6 (Interleukin 6) rather than IFNγ, is identified as the main candidate cytokine regulating such an immune/MER41/cognition pathway. Of note, differences between humans and chimpanzees are observed regarding the insertion sites of MER41 LTRs in the promoter regions of ID-associated genes. Finally, a survey of the human proteome has allowed us to map a protein-protein network which links the identified immune/MER41/cognition pathway to FOXP2 (Forkhead Box P2), a key TF involved in the emergence of human speech. Our work suggests that together with the evolution of immune genes, the stepped self-domestication of MER41 in the genomes of primates could have contributed to cognitive evolution. We further propose that non-inherited forms of ID might result from the untimely or quantitatively inappropriate expression of immune signals, notably IL-6, that putatively regulate cognition-associated genes via promoter-localized MER41 LTRs.
History
References
- https://doi.org//10.1186/2040-2392-4-36
- https://doi.org//10.1093/nar/gku1205
- https://doi.org//10.1038/75556
- https://doi.org//10.1016/j.bbr.2009.01.013
- https://doi.org//10.3389/fnmol.2015.00084
- https://doi.org//10.1093/database/bau012
- https://doi.org//10.1093/nar/gku1204
- https://doi.org//10.1016/j.nbd.2006.05.001
- https://doi.org//10.1126/science.aad5497
- https://doi.org//10.1186/gb-2007-8-4-r64
- https://doi.org//10.1093/molbev/mst080
- https://doi.org//10.1093/nar/gkx1081
- https://doi.org//10.1101/514943
- https://doi.org//10.1016/j.ajhg.2015.11.014
- https://doi.org//10.1016/j.coviro.2013.08.005
- https://doi.org//10.1002/ana.22149
- https://doi.org//10.3389/fmicb.2017.01986
- https://doi.org//10.1523/JNEUROSCI.2663-16.2018
- https://doi.org//10.1016/j.cell.2009.03.041
- https://doi.org//10.1126/science.1105136
- https://doi.org//10.1038/nature11247
- https://doi.org//10.1093/hmg/ddy035
- https://doi.org//10.1074/mcp.M113.035600
- https://doi.org//10.1038/nature18626
- https://doi.org//10.1016/j.tig.2009.03.002
- https://doi.org//10.1016/j.ajhg.2017.05.006
- https://doi.org//10.1074/jbc.R116.774745
- https://doi.org//10.1016/j.ajhg.2013.05.007
- https://doi.org//10.1016/j.neuropharm.2014.10.023
- https://doi.org//10.1016/j.jaci.2008.03.012
- https://doi.org//10.1016/j.neuron.2012.01.005
- https://doi.org//10.1038/ncomms10789
- https://doi.org//10.1371/journal.pgen.1006883
- https://doi.org//10.1146/annurev-virology-100114-054945
- https://doi.org//10.1101/cshperspect.a001271
- https://doi.org//10.1016/j.ajhg.2015.11.024
- https://doi.org//10.1038/nature08549
- https://doi.org//10.1002/ana.23970
- https://doi.org//10.1093/bioinformatics/bts084
- https://doi.org//10.1093/nar/gkw377
- https://doi.org//10.1016/j.molmed.2018.02.007
- https://doi.org//10.3389/fncel.2014.00391
- https://doi.org//10.1038/s41398-018-0114-x
- https://doi.org//10.1038/sj.cdd.4401837
- https://doi.org//10.1016/j.tins.2004.11.002
- https://doi.org//10.3389/fnins.2017.00582
- https://doi.org//10.12688/f1000research.10950.1
- https://doi.org//10.3389/fncel.2017.00212
- https://doi.org//10.1093/database/bay003
- https://doi.org//10.1016/j.ymeth.2014.11.020
- https://doi.org//10.1016/S1471-4906(01)02118-4
- https://doi.org//10.1038/nature14248
- https://doi.org//10.1093/nar/gku1177
- https://doi.org//10.1016/j.jphysparis.2014.05.002
- https://doi.org//10.7717/peerj.1054
- https://doi.org//10.1098/rstb.2011.0001
- https://doi.org//10.1093/nar/gkv1310
- https://doi.org//10.1007/s12031-014-0359-7
- https://doi.org//10.3389/fnmol.2016.00118
- https://doi.org//10.1086/522237
- https://doi.org//10.1073/pnas.0400782101
- https://doi.org//10.1093/nar/gkw1108
- https://doi.org//10.1093/nar/gky1055
- https://doi.org//10.1093/nar/gky092
- https://doi.org//10.1371/journal.pone.0177119
- https://doi.org//10.1371/journal.pgen.1002145
- https://doi.org//10.1086/522238
- https://doi.org//10.1186/1742-2094-7-77
- https://doi.org//10.1074/jbc.M207174200
- https://doi.org//10.1073/pnas.1721820115
- https://doi.org//10.1016/j.neuron.2015.11.013
Usage metrics
Read the peer-reviewed publication
Categories
- Gene and Molecular Therapy
- Biomarkers
- Genetics
- Genetically Modified Animals
- Developmental Genetics (incl. Sex Determination)
- Epigenetics (incl. Genome Methylation and Epigenomics)
- Gene Expression (incl. Microarray and other genome-wide approaches)
- Livestock Cloning
- Genome Structure and Regulation
- Genetic Engineering
- Genomics