Human-specific histone methylation signatures at transcription start sites in prefrontal neurons.
Cognitive abilities and disorders unique to humans are thought to result from adaptively driven changes in brain transcriptomes, but little is known about the role of cis-regulatory changes affecting transcription start sites (TSS). Here, we mapped in human, chimpanzee, and macaque prefrontal cortex...
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2012
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oai:doaj.org-article:c30b9fddce6b4bb48ac08d60aa858ebe2021-11-18T05:37:22ZHuman-specific histone methylation signatures at transcription start sites in prefrontal neurons.1544-91731545-788510.1371/journal.pbio.1001427https://doaj.org/article/c30b9fddce6b4bb48ac08d60aa858ebe2012-01-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/23185133/pdf/?tool=EBIhttps://doaj.org/toc/1544-9173https://doaj.org/toc/1545-7885Cognitive abilities and disorders unique to humans are thought to result from adaptively driven changes in brain transcriptomes, but little is known about the role of cis-regulatory changes affecting transcription start sites (TSS). Here, we mapped in human, chimpanzee, and macaque prefrontal cortex the genome-wide distribution of histone H3 trimethylated at lysine 4 (H3K4me3), an epigenetic mark sharply regulated at TSS, and identified 471 sequences with human-specific enrichment or depletion. Among these were 33 loci selectively methylated in neuronal but not non-neuronal chromatin from children and adults, including TSS at DPP10 (2q14.1), CNTN4 and CHL1 (3p26.3), and other neuropsychiatric susceptibility genes. Regulatory sequences at DPP10 and additional loci carried a strong footprint of hominid adaptation, including elevated nucleotide substitution rates and regulatory motifs absent in other primates (including archaic hominins), with evidence for selective pressures during more recent evolution and adaptive fixations in modern populations. Chromosome conformation capture at two neurodevelopmental disease loci, 2q14.1 and 16p11.2, revealed higher order chromatin structures resulting in physical contact of multiple human-specific H3K4me3 peaks spaced 0.5-1 Mb apart, in conjunction with a novel cis-bound antisense RNA linked to Polycomb repressor proteins and downregulated DPP10 expression. Therefore, coordinated epigenetic regulation via newly derived TSS chromatin could play an important role in the emergence of human-specific gene expression networks in brain that contribute to cognitive functions and neurological disease susceptibility in modern day humans.Hennady P ShulhaJessica L CrisciDenis ReshetovJogender S TushirIris CheungRahul BharadwajHsin-Jung ChouIsaac B HoustonCyril J PeterAmanda C MitchellWei-Dong YaoRichard H MyersJiang-Fan ChenTodd M PreussEvgeny I RogaevJeffrey D JensenZhiping WengSchahram AkbarianPublic Library of Science (PLoS)articleBiology (General)QH301-705.5ENPLoS Biology, Vol 10, Iss 11, p e1001427 (2012) |
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Biology (General) QH301-705.5 |
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Biology (General) QH301-705.5 Hennady P Shulha Jessica L Crisci Denis Reshetov Jogender S Tushir Iris Cheung Rahul Bharadwaj Hsin-Jung Chou Isaac B Houston Cyril J Peter Amanda C Mitchell Wei-Dong Yao Richard H Myers Jiang-Fan Chen Todd M Preuss Evgeny I Rogaev Jeffrey D Jensen Zhiping Weng Schahram Akbarian Human-specific histone methylation signatures at transcription start sites in prefrontal neurons. |
| description |
Cognitive abilities and disorders unique to humans are thought to result from adaptively driven changes in brain transcriptomes, but little is known about the role of cis-regulatory changes affecting transcription start sites (TSS). Here, we mapped in human, chimpanzee, and macaque prefrontal cortex the genome-wide distribution of histone H3 trimethylated at lysine 4 (H3K4me3), an epigenetic mark sharply regulated at TSS, and identified 471 sequences with human-specific enrichment or depletion. Among these were 33 loci selectively methylated in neuronal but not non-neuronal chromatin from children and adults, including TSS at DPP10 (2q14.1), CNTN4 and CHL1 (3p26.3), and other neuropsychiatric susceptibility genes. Regulatory sequences at DPP10 and additional loci carried a strong footprint of hominid adaptation, including elevated nucleotide substitution rates and regulatory motifs absent in other primates (including archaic hominins), with evidence for selective pressures during more recent evolution and adaptive fixations in modern populations. Chromosome conformation capture at two neurodevelopmental disease loci, 2q14.1 and 16p11.2, revealed higher order chromatin structures resulting in physical contact of multiple human-specific H3K4me3 peaks spaced 0.5-1 Mb apart, in conjunction with a novel cis-bound antisense RNA linked to Polycomb repressor proteins and downregulated DPP10 expression. Therefore, coordinated epigenetic regulation via newly derived TSS chromatin could play an important role in the emergence of human-specific gene expression networks in brain that contribute to cognitive functions and neurological disease susceptibility in modern day humans. |
| format |
article |
| author |
Hennady P Shulha Jessica L Crisci Denis Reshetov Jogender S Tushir Iris Cheung Rahul Bharadwaj Hsin-Jung Chou Isaac B Houston Cyril J Peter Amanda C Mitchell Wei-Dong Yao Richard H Myers Jiang-Fan Chen Todd M Preuss Evgeny I Rogaev Jeffrey D Jensen Zhiping Weng Schahram Akbarian |
| author_facet |
Hennady P Shulha Jessica L Crisci Denis Reshetov Jogender S Tushir Iris Cheung Rahul Bharadwaj Hsin-Jung Chou Isaac B Houston Cyril J Peter Amanda C Mitchell Wei-Dong Yao Richard H Myers Jiang-Fan Chen Todd M Preuss Evgeny I Rogaev Jeffrey D Jensen Zhiping Weng Schahram Akbarian |
| author_sort |
Hennady P Shulha |
| title |
Human-specific histone methylation signatures at transcription start sites in prefrontal neurons. |
| title_short |
Human-specific histone methylation signatures at transcription start sites in prefrontal neurons. |
| title_full |
Human-specific histone methylation signatures at transcription start sites in prefrontal neurons. |
| title_fullStr |
Human-specific histone methylation signatures at transcription start sites in prefrontal neurons. |
| title_full_unstemmed |
Human-specific histone methylation signatures at transcription start sites in prefrontal neurons. |
| title_sort |
human-specific histone methylation signatures at transcription start sites in prefrontal neurons. |
| publisher |
Public Library of Science (PLoS) |
| publishDate |
2012 |
| url |
https://doaj.org/article/c30b9fddce6b4bb48ac08d60aa858ebe |
| work_keys_str_mv |
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| _version_ |
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