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

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 Jensen, Zhiping Weng, Schahram Akbarian

Research output: Contribution to journalArticle

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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 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.

Original languageEnglish (US)
Article numbere1001427
JournalPLoS Biology
Volume10
Issue number11
DOIs
StatePublished - Nov 2012
Externally publishedYes

Fingerprint

Methylation
Transcription Initiation Site
histones
methylation
Histones
Neurons
transcription (genetics)
neurons
Chromatin
chromatin
Brain
Genes
Hominidae
Repressor Proteins
Epigenomics
epigenetics
Antisense RNA
loci
Chromosomes
Gene expression

ASJC Scopus subject areas

  • Agricultural and Biological Sciences(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Immunology and Microbiology(all)
  • Neuroscience(all)

Cite this

Shulha, H. P., Crisci, J. L., Reshetov, D., Tushir, J. S., Cheung, I., Bharadwaj, R., ... Akbarian, S. (2012). Human-Specific Histone Methylation Signatures at Transcription Start Sites in Prefrontal Neurons. PLoS Biology, 10(11), [e1001427]. https://doi.org/10.1371/journal.pbio.1001427

Human-Specific Histone Methylation Signatures at Transcription Start Sites in Prefrontal Neurons. / Shulha, Hennady P.; Crisci, Jessica L.; Reshetov, Denis; Tushir, Jogender S.; Cheung, Iris; Bharadwaj, Rahul; Chou, Hsin Jung; Houston, Isaac B.; Peter, Cyril J.; Mitchell, Amanda C.; Yao, Wei Dong; Myers, Richard H.; Chen, Jiang fan; Preuss, Todd M.; Rogaev, Evgeny I.; Jensen, Jeffrey; Weng, Zhiping; Akbarian, Schahram.

In: PLoS Biology, Vol. 10, No. 11, e1001427, 11.2012.

Research output: Contribution to journalArticle

Shulha, HP, Crisci, JL, Reshetov, D, Tushir, JS, Cheung, I, Bharadwaj, R, Chou, HJ, Houston, IB, Peter, CJ, Mitchell, AC, Yao, WD, Myers, RH, Chen, JF, Preuss, TM, Rogaev, EI, Jensen, J, Weng, Z & Akbarian, S 2012, 'Human-Specific Histone Methylation Signatures at Transcription Start Sites in Prefrontal Neurons', PLoS Biology, vol. 10, no. 11, e1001427. https://doi.org/10.1371/journal.pbio.1001427
Shulha HP, Crisci JL, Reshetov D, Tushir JS, Cheung I, Bharadwaj R et al. Human-Specific Histone Methylation Signatures at Transcription Start Sites in Prefrontal Neurons. PLoS Biology. 2012 Nov;10(11). e1001427. https://doi.org/10.1371/journal.pbio.1001427
Shulha, Hennady P. ; Crisci, Jessica L. ; Reshetov, Denis ; Tushir, Jogender S. ; Cheung, Iris ; Bharadwaj, Rahul ; Chou, Hsin Jung ; Houston, Isaac B. ; Peter, Cyril J. ; Mitchell, Amanda C. ; Yao, Wei Dong ; Myers, Richard H. ; Chen, Jiang fan ; Preuss, Todd M. ; Rogaev, Evgeny I. ; Jensen, Jeffrey ; Weng, Zhiping ; Akbarian, Schahram. / Human-Specific Histone Methylation Signatures at Transcription Start Sites in Prefrontal Neurons. In: PLoS Biology. 2012 ; Vol. 10, No. 11.
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