Brain

About 8% of the human genome is composed of endogenous retroviruses. According to a new study published in the journal Cell Reports, these retroviruses may have played a significant role in the development of the human brain as well as in various neurological diseases, such as ALS, schizophrenia and bipolar disorder.

Brattas et al. report that ERVs are bound by TRIM28 in human neural progenitor cells. This results in the establishment of local heterochromatin that affects nearby gene expression, suggesting a role for ERVs in the control of transcriptional networks in the developing human brain. Interestingly, ERVs bound by TRIM28 are mostly enriched for elements that integrated around 35–55 million years ago, thus not binding to the most recent ERVs as well as ancient elements. Image credit: Per Ludvik Brattas et al, doi: 10.1016/j.celrep.2016.12.010.

“Endogenous retroviruses (ERVs) have existed in the human genome for millions of years,” the authors said.

“They can be found in a part of DNA that was previously considered unimportant, so called junk-DNA — a notion that researchers have now started to reconsider.”

“The genes that control the production of various proteins in the body represent a smaller proportion of our DNA than ERVs,” added Dr. Johan Jakobsson, a researcher at Lund University, Sweden, and corresponding author of the study.

“They account for approximately 2%, while ERVs account for at least 8 % of the total genome.”

“If it turns out that ERVs are able to influence the production of proteins, this will provide us with a huge new source of information about the human brain.”

And this is precisely what Dr. Jakobsson and his colleagues from Lund University, Karolinska Institute and Uppsala University discovered.

Almost 10,000 ERVs, according to the team, may serve as ‘docking platforms’ for a protein called TRIM28.

This protein has the ability to ‘switch off’ not only viruses but also the standard genes adjacent to them in the DNA helix, allowing the presence of ERVs to affect gene expression.

The switching-off mechanism may behave differently in different people, since retroviruses are a type of genetic material that may end up in different places of the genome.

“In this study, we find a region- and developmental stage-specific expression pattern of ERVs in the developing human embryonic CNS (central nervous system), which is linked to a gene regulatory network involving ERVs,” the authors said.

“We demonstrate that several thousand ERVs, many that are primate specific, act as docking platforms for the epigenetic co-repressor protein TRIM28, which results in the establishment of local heterochromatin around these ERVs.”

“This repressive transcriptional network modulates expression of protein-coding transcripts important for brain development, thereby providing an additional layer of transcriptional regulation.”

Two years ago, Dr. Jakobsson’s team showed that ERVs had a regulatory role in neurons specifically.

However, that study was conducted on mice, whereas the current study was made using human cells. The differences between mice and humans are particularly important in this context.

Many of the retroviruses that have been built into the human DNA do not exist in species other than humans and our closest relatives — gorillas and chimpanzees. They seem to have incorporated themselves into the genome some 35–45 million years ago, when the evolutionary lineage of primates was divided between the Old and New World.

“Our findings open up for several exciting future studies on the role of ERVs as potential drivers of human brain evolution, their contribution to individual variation, and the implication in human brain disorders,” the researchers concluded.

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Per Ludvik Brattas et al. 2017. TRIM28 Controls a Gene Regulatory Network Based on Endogenous Retroviruses in Human Neural Progenitor Cells. Cell Reports 18 (1): 1-11; doi: 10.1016/j.celrep.2016.12.010

This article is based on a press-release from Lund University.

e retroviruses may have played a significant role in the development of the human brain as well as in various neurological diseases, such as ALS, schizophrenia and bipolar disorder.

Brattas et al. report that ERVs are bound by TRIM28 in human neural progenitor cells. This results in the establishment of local heterochromatin that affects nearby gene expression, suggesting a role for ERVs in the control of transcriptional networks in the developing human brain. Interestingly, ERVs bound by TRIM28 are mostly enriched for elements that integrated around 35–55 million years ago, thus not binding to the most recent ERVs as well as ancient elements. Image credit: Per Ludvik Brattas et al, doi: 10.1016/j.celrep.2016.12.010.

“Endogenous retroviruses (ERVs) have existed in the human genome for millions of years,” the authors said.

“They can be found in a part of DNA that was previously considered unimportant, so called junk-DNA — a notion that researchers have now started to reconsider.”

“The genes that control the production of various proteins in the body represent a smaller proportion of our DNA than ERVs,” added Dr. Johan Jakobsson, a researcher at Lund University, Sweden, and corresponding author of the study.

“They account for approximately 2%, while ERVs account for at least 8 % of the total genome.”

“If it turns out that ERVs are able to influence the production of proteins, this will provide us with a huge new source of information about the human brain.”

And this is precisely what Dr. Jakobsson and his colleagues from Lund University, Karolinska Institute and Uppsala University discovered.

Almost 10,000 ERVs, according to the team, may serve as ‘docking platforms’ for a protein called TRIM28.

This protein has the ability to ‘switch off’ not only viruses but also the standard genes adjacent to them in the DNA helix, allowing the presence of ERVs to affect gene expression.

The switching-off mechanism may behave differently in different people, since retroviruses are a type of genetic material that may end up in different places of the genome.

“In this study, we find a region- and developmental stage-specific expression pattern of ERVs in the developing human embryonic CNS (central nervous system), which is linked to a gene regulatory network involving ERVs,” the authors said.

“We demonstrate that several thousand ERVs, many that are primate specific, act as docking platforms for the epigenetic co-repressor protein TRIM28, which results in the establishment of local heterochromatin around these ERVs.”

“This repressive transcriptional network modulates expression of protein-coding transcripts important for brain development, thereby providing an additional layer of transcriptional regulation.”

Two years ago, Dr. Jakobsson’s team showed that ERVs had a regulatory role in neurons specifically.

However, that study was conducted on mice, whereas the current study was made using human cells. The differences between mice and humans are particularly important in this context.

Many of the retroviruses that have been built into the human DNA do not exist in species other than humans and our closest relatives — gorillas and chimpanzees. They seem to have incorporated themselves into the genome some 35–45 million years ago, when the evolutionary lineage of primates was divided between the Old and New World.

“Our findings open up for several exciting future studies on the role of ERVs as potential drivers of human brain evolution, their contribution to individual variation, and the implication in human brain disorders,” the researchers concluded.

_____

Per Ludvik Brattas et al. 2017. TRIM28 Controls a Gene Regulatory Network Based on Endogenous Retroviruses in Human Neural Progenitor Cells. Cell Reports 18 (1): 1-11; doi: 10.1016/j.celrep.2016.12.010

This article is based on a press-release from Lund University.