Human-Specific Histone Methylation Signatures at Transcription Start Sites in Prefrontal Neurons

• Authors: Hennady P. Shulha, University of Massachusetts Medical School; Jessica L. Crisci, University of Massachusetts Medical School; Denis Reshetov, Vavilov Institute of General Genetics; Jogender S. Tushir, University of Massachusetts Medical School; Iris Cheung, University of Massachusetts Medical School; Rahul Bharadwaj, University of Massachusetts Medical School; Hsin-Jung Chou, University of Massachusetts Medical School; Isaac B. Houston, University of Massachusetts Medical School; Cyril J. Peter, University of Massachusetts Medical School; Amanda C. Mitchell, University of Massachusetts Medical School; Wei-Dong Yao, New England Primate Center; Richard H. Myers, Boston University; Jiang-Fan Chen, Boston University; Todd Preuss, Emory University; Evgeny I. Rogaev, Vavilov Institute of General Genetics; Jeffrey D. Jensen, University of Massachusetts Medical School; Zhiping Weng, University of Massachusetts Medical School; Schahram Akbarian, University of Massachusetts Medical School
• Journal Title: PLoS Biology
• Volume: Volume 10, Number 11
• Publisher: Public Library of Science | 2012-11-01, Pages e1001427-e1001427
• Type of Work: Article | Final Publisher PDF
• Publisher DOI: http://doi.org/10.1371/journal.pbio.1001427
• Subjects: Biology, Bioinformatics; Biology, Neuroscience
• Keywords: Adult; Animals; Base Sequence; Child; Chromatin; Chromatin Assembly and Disassembly; Chromosome Mapping; Cognition; Contactins; DNA Methylation; Dipeptidyl-Peptidases and Tripeptidyl-Peptidases; Epigenesis, Genetic; Evolution, Molecular; Gene Regulatory Networks; Genetic Loci; Histones; Humans; Lysine; Macaca; Mental Disorders; Neurons; Pan troglodytes; Phylogeny; Polycomb-Group Proteins; Prefrontal Cortex; Regulatory Sequences, Nucleic Acid; Species Specificity; Transcription Initiation Site; Transcription, Genetic

Abstract

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 neur odevelopmental 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.