Brain 3D genome study uncovers human-specific regulatory changes during development

January 28, 2021

A team led by Prof. SU Bing from the Kunming Institute of Zoology (KIZ) of the Chinese Academy of Sciences (CAS), Prof. LI Cheng from Peking University, and Prof. ZHANG Shihua from the Academy of Mathematics and Systems Science of CAS has reported the highest resolution by far of the 3D genome of the primate brain, and demonstrated the molecular regulatory mechanisms of human brain evolution through cross-species multi-omics analysis and experimental validation. The study was published in Cell.

The unique pattern of human brain development stems from accumulated genetic changes during human evolution. Among the huge number of diverging genetic changes, only a small portion of the between-species changes have been functionally important. The challenge is to identify the causal changes responsible for the unique pattern of human brain development and their regulatory mechanisms. Macaque monkeys, genetically similar to humans, are the ideal model for studying the origin and developmental mechanisms of the human brain.

The genome of mammalian species including humans is about two meters long and is compiled in the nucleus with a diameter of only 10 micrometers. This nonrandom compilation is characterized by organized three-dimensional (3D) distribution, which is important for cell proliferation and differentiation during development. Recently, the invention of whole-genome chromosomal structure capture technology (referred to as Hi-C) provides a great opportunity for dissecting the fine-tuned organization of the genome during brain development.

In this study, the researchers conducted cross-species analyses of brain 3D genomes through cross-disciplinary collaboration.

They first constructed a high-resolution 3D chromatin structure map of the macaque fetal brain using the Hi-C technique. Reaching a 1.5 kb resolution, this Hi-C map represents the highest resolution of primate brains so far achieved, and it has become a useful omics dataset for revealing the 3D genome organization in detail. Meanwhile, the researchers generated a transcriptome map, a chromatin open region map and a map of the anchor protein CCCTC-binding factor (CTCF).

Based on these multi-omics data, the researchers constructed for the first time a fine map of the chromatin structure of the macaque fetal brain and identified the chromatin structure in different scales, including compartments, topologically associating domains (TADs) and chromatin loops. They also identified regulatory elements in the genome such as enhancers.

Using published human and mouse brain Hi-C data, they then performed a cross-species comparisons, and discovered many human-specific chromatin structural changes, including 499 human-specific TADs and 1266 human-specific loops. Notably, the human-specific loops were shown to be enriched with enhancer-enhancer interactions, representing the origin of a mechanism for fine-tuning brain development during human evolution.

Based on the analysis of single-cell transcriptome data on human brain development, the researchers observed that these human-specific loop-related genes are highly expressed in the subplate lamina, a transient zone of the developing brain critical for neural circuit formation and plasticity. The subplate lamina had been found to show an extradentary expansion compared to that of the macaque and mouse, and is about four times the thickness of the cortical plate. The subplate starts to decrease after birth and eventually disappears, and little is known about this transient zone. This finding provides the first evidence for the key role of the subplate in forming human-specific brain structures during development.

In addition, the researchers discovered that many human-specific mutations (e.g., point mutations and structural changes) are located in the TAD boundary and loop anchor regions, which may lead to the origin of novel binding sites of transcriptional factors and human-specific chromatin structures.

The researchers studied an example involving the EPHA7 gene, which is highly expressed in the subplate and is critical for neuronal dendrite development. The human-specific point mutations of EPHA7 lead to the formation of human-specific enhancers and loops. Through an experiment involving enhancer knockout in cell lines, they proved that human-specific EPHA7 enhancers can cause regulatory changes in EPHA7 expression and affect dendrite development.

This study sheds new light on the genetic mechanisms of human brain origin and serves as a valuable resource for 3D brain genomes.

Chinese Academy of Sciences Headquarters

Related Genome Articles from Brightsurf:

Genome evolution goes digital
Dr. Alan Herbert from InsideOutBio describes ground-breaking research in a paper published online by Royal Society Open Science.

Breakthrough in genome visualization
Kadir Dede and Dr. Enno Ohlebusch at Ulm University in Germany have devised a method for constructing pan-genome subgraphs at different granularities without having to wait hours and days on end for the software to process the entire genome.

Sturgeon genome sequenced
Sturgeons lived on earth already 300 million years ago and yet their external appearance seems to have undergone very little change.

A sea monster's genome
The giant squid is an elusive giant, but its secrets are about to be revealed.

Deciphering the walnut genome
New research could provide a major boost to the state's growing $1.6 billion walnut industry by making it easier to breed walnut trees better equipped to combat the soil-borne pathogens that now plague many of California's 4,800 growers.

Illuminating the genome
Development of a new molecular visualisation method, RNA-guided endonuclease -- in situ labelling (RGEN-ISL) for the CRISPR/Cas9-mediated labelling of genomic sequences in nuclei and chromosomes.

A genome under influence
References form the basis of our comprehension of the world: they enable us to measure the height of our children or the efficiency of a drug.

How a virus destabilizes the genome
New insights into how Kaposi's sarcoma-associated herpesvirus (KSHV) induces genome instability and promotes cell proliferation could lead to the development of novel antiviral therapies for KSHV-associated cancers, according to a study published Sept.

Better genome editing
Reich Group researchers develop a more efficient and precise method of in-cell genome editing.

Unlocking the genome
A team led by Prof. Stein Aerts (VIB-KU Leuven) uncovers how access to relevant DNA regions is orchestrated in epithelial cells.

Read More: Genome News and Genome Current Events is a participant in the Amazon Services LLC Associates Program, an affiliate advertising program designed to provide a means for sites to earn advertising fees by advertising and linking to