Gene Regulator in Brain’s Executive Hub Tracked Across Lifespan

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Gene regulator in brain's executive hub tracked across lifespan — NIH study

Mental illness suspect genes are among the most environmentally responsive.

For the first time, scientists have tracked the activity,  across the lifespan, of an environmentally responsive regulatory mechanism that  turns genes on and off in the brain's executive hub. Among key findings of the  study by National Institutes of Health scientists: genes implicated in  schizophrenia and autism turn out to be members of a select club of genes in  which regulatory activity peaks during an environmentally-sensitive critical  period in development. The mechanism, called DNA  methylation,  abruptly switches from off to on within the human brain's prefrontal cortex  during this pivotal transition from fetal to postnatal life. As methylation  increases, gene expression slows down after birth.

Epigenetic mechanisms like methylation leave chemical instructions that tell genes what  proteins to make –what kind of tissue to produce or what functions to activate.  Although not part of our DNA, these instructions are inherited from our  parents. But they are also influenced by environmental factors, allowing for  change throughout the lifespan.

“Developmental brain disorders may be traceable to  altered methylation of genes early in life,” explained Barbara Lipska, Ph.D., a  scientist in the NIH’s National Institute of Mental Health (NIMH) and lead  author of the study. “For example, genes that code for the enzymes that carry  out methylation have been implicated in schizophrenia. In the prenatal  brain, these genes help to shape developing circuitry for learning, memory and  other executive functions which become disturbed in the disorders. Our study  reveals that methylation in a family of these genes changes dramatically during  the transition from fetal to postnatal life – and that this process is  influenced by methylation itself, as well as genetic variability. Regulation of these genes may be particularly sensitive to environmental  influences during this critical early life period.”

Lipska and colleagues report on the ebb and flow of the  human prefrontal cortex's (PFC) epigenome across the lifespan, February 2,  2012, online in the American Journal of Human Genetics.

“This  new study reminds us that genetic sequence is only part of the story of  development. Epigenetics links nurture and nature, showing us when and  where the environment can influence how the genetic sequence is read,” said  NIMH director Thomas R. Insel, M.D.

In a companion  study published last October, the NIMH researchers traced expression of gene products  in the PFC across the lifespan. The current study instead examined methylation  at 27,000 sites within PFC genes that regulate such expression. Both studies  examined post-mortem brains of non-psychiatrically impaired individuals ranging  in age from two weeks after conception to 80 years old.

Chart of PFC methylation across lifespan

Two representative genes show strikingly opposite trajectories of PFC methylation across the lifespan. Each dot represents a different brain. Usually, the more methylation, the less gene expression. Source: Barbara Lipska, Ph.D., NIMH Clinical Brain Disorders Branch.

In most cases, when chemicals called methyl groups attach  to regulatory regions of genes, they silence them. Usually, the more  methylation, the less gene expression.Lipska's team found that the  overall level of PFC methylation is low prenatally when gene expression is  highest and then switches direction at birth, increasing as gene expression  plummets in early childhood. It then levels off as we grow older. But methylation in some genes shows an opposite trajectory. The study  found that methylation is strongly influenced by gender, age and genetic  variation.

For example, methylation levels differed between males  and females in 85 percent of X chromosome sites examined, which may help to  explain sex differences in disorders like autism and schizophrenia.

Different genes — and subsets of genes — methylate at  different ages. Some of the suspect genes found to peak in methylation around  birth code for enzymes, called methytransferases, that are over-expressed in  people with schizophrenia and bipolar disorder. This process is  influenced, in turn, by methylation in other genes, as well as by genetic  variation. So genes associated with risk for such psychiatric disorders  may influence gene expression through methylation in addition to inherited DNA.

Chart of PFC methylation across lifespan by gender.

A representative gene showing how sex can influence levels of methylation across the lifespan. Each dot represents a different brain. Source: Barbara Lipska, Ph.D., NIMH Clinical Brain Disorders Branch.

Scientists worldwide can now mine a newly created online  database of PFC lifespan DNA methylation from the study. The data are  accessible to qualified researchers at: BrainCloud, a web browser application developed by NIMH  to interrogate the study data, can be downloaded at

The mission of the NIMH is to transform the understanding and treatment of mental illnesses through basic and clinical research, paving the way for prevention, recovery and cure. For more information, visit the NIMH website.

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The above story is reprinted from materials provided by National Institutes of Health.

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