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Human-Specific Histone Methylation Signatures Found in Prefrontal Cortex

NEW YORK (GenomeWeb News) – There are hundreds of genomic regions that are uniquely regulated in the human brain as compared to other primates, an international team of researchers reported in PLOS Biology this week.

The researchers homed in on the prefrontal cortex of the brain as it is involved in complex cognitive functions, and changes to its transcriptome are thought to be behind human cognitive abilities as well as disorders.

Researchers led by Schahram Akbarian from the University of Massachusetts Medical School and Mount Sinai School of Medicine in New York City examined the distribution of the histone H3-trimethyl-lysine 4, or H3K4me3, epigenetic mark in prefrontal cortex tissue samples from humans, chimpanzees, and macaques. H3K4me3 is a transcriptional activating mark found at transcription start sites.

The researchers identified 471 sequences that were specifically enriched or deleted in human samples. Of those, 33 were selectively methylated in neuronal chromatin, including DPP10, CNTN4, and CHL1. DPP10, the researchers reported, also appears to be under selective pressure, in addition to being thought to play a role in a handful of cognitive and psychiatric disorders.

"Much about human biology and disease cannot be deduced by simply sequencing the genome," said Akbarian in a statement. "Mapping the epigenome of neurons and other cells will help us to better understand the inner workings of our brain, and where we are coming from."

The researchers performed cell-type specific epigenomic profiling — using neuron nucleus antigen-based immunotagging and fluorescence-activated sorting — and deep sequencing of H3K4me3-tagged neuronal nucleosomes to tease out human-specific H3K4me3 regulatory changes to gene expression in primate brains. From this, they gathered the H3K4me3 epigenomes of 11 humans — four adults and seven children — four mature chimpanzees, and three mature macaques.

More than 400 H3K4me3 peaks were enriched in human as compared to the chimpanzees and macaques, and another 50 were depleted in humans.

Of those hundreds of peaks, 33 were selectively enriched in prefrontal cortex chromatin, and two peaks were near DPP10. The researchers noted that structural variants of DPP10 have been linked to risk for autism while common variants in that gene are linked to bipolar disorder, schizophrenia, and asthma risk.

Many of the human-specific epigenetic peaks occurred in clusters, and the researchers hypothesized that pairs of H3K4me3 peaks could be contained in chromatin loops and other higher-order structures.

To test this idea, they searched a database containing data from chromatin interaction analysis by paired-end tag sequencing studies that are used to find chromosomal loopings bound by the Pol II initiation complex. They found three interactions that matched their peaks, which they then confirmed through a chromosome conformation capture approach.

"We conclude that human-specific H3K4me3 peaks spaced as far apart as 1 Mb are potentially co-regulated and physically interact via chromatin loopings and other higher order chromatin structures," the researchers wrote.

Additionally, the researchers specifically tested DPP10 looping, finding that looping brought the two DPP10 peaks into direct contact.

To determine whether H3K4 methylation at DPP10 led to changes in gene expression levels, the researchers performed RNA sequencing of three adult human prefrontal cortexes and compared that to data from chimps and macaques and to RT-PCR data from other human prefrontal cortex samples. The researchers reported that an antisense DPP10 transcript was expressed at higher levels in humans than in other primates. Expression was also localized to a subset of the neuronal layers.

The researchers also reported that DPP10 and a few other peaks showed increased rates of nucleotide substitutions and other signs of positive selection. However, the researchers cautioned that "the overwhelming majority of sites with human-specific H3K4me3 changes did not show evidence for recent adaptive fixations in the surrounding DNA."

"Therefore, and perhaps not unsurprisingly, neuronal histone methylation mapping in human, chimpanzee, and macaque primarily reveals information about changes in epigenetic decoration of regulatory sequences in the hominid genome after our lineage split from the common ancestor shared with present-day non-human primates," they added.

All told, the researchers said that "coordinated epigenetic regulation via newly derived [transcriptional start site] 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."

The researchers also noted a few limitations to their study. For their analyses, they used prefrontal cortex samples from both human adults and children to compare across species, but they said that within the species, "signatures in the cortical transcriptome are thought to be even more pronounced during pre- and perinatal development." There could be more signatures or more pronounced signatures in younger brains.

They added that other regions of the cortex could also show human-specific methylation.

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