Summary: UT Southwestern researchers discover a gene implicated in circadian rhythm may also play a vital role in regulating genes important for our brain evolution.
Source: UT Southwestern Medical Center.
Scientists have long sought to unravel the molecular mysteries that make the human brain special: What processes drove its evolution through the millennia? Which genes are critical to cognitive development?
A new study provides insight on the matter by demonstrating that a gene controlling our biological clocks also plays a vital role in regulating human-specific genes important to brain evolution. The findings from the O’Donnell Brain Institute open new paths of research into how CLOCK proteins produced by the CLOCK gene affect brain function and the processes by which neurons find their proper place in the brain.
“People have been searching for genes that are important for brain evolution, within the context of our larger, folded brains,” said Dr. Genevieve Konopka, a neuroscientist with UT Southwestern’s Peter O’Donnell Jr. Brain Institute. “We now have evidence that CLOCK regulates many genes outside of circadian rhythms, so we can place it as a key point in the hierarchy of important molecular pathways for human brain development and evolution.”
Human brains are notably bigger than the brains of our closest relative, the chimpanzee. But because size alone doesn’t account for cognitive abilities – mammals such as whales and dolphins have larger brains – scientists have sought to understand what makes the human brain smarter.
Dr. Konopka’s research has focused on the neocortex, an area of the brain with distinctive folds that is associated with sight and hearing and considered the most recently evolved part of the cortex. Her lab released a study in 2012 that found CLOCK has increased expression in the human neocortex compared to other primate brains. The findings prompted further questions about what these body-clock proteins were doing in a neural region that is not traditionally considered a hub for circadian rhythm function.
The new study published in Genes & Development offers some answers:
- CLOCK regulates a set of genes important to brain evolution that have differences in terms of where and how much they are expressed compared to other primates.
CLOCK regulates genes linked to cognitive disorders, and has an important role in human neuronal migration – the process by which neurons born in other parts of the brain travel to the appropriate neural circuits. Defects in this migration process lead to a range of cognitive disorders.
The findings suggest there may be much more to learn about various functions controlled by CLOCK, identified in 1997 by UT Southwestern’s Dr. Joseph S. Takahashi. His groundbreaking discovery expanded on Nobel Prize-winning fruit fly research by showing biological clocks exist in mammals. Multiple studies since Dr. Takahashi’s finding have suggested links between CLOCK function and health issues such as cancer, cognitive disorders, and depression.
Dr. Konopka’s study – which used postmortem brain tissue and human neurons in culture – is the first to examine CLOCK’s role in the human neocortex.
“A novel function of the CLOCK gene in the brain not directly related to circadian rhythms is unexpected, and its possible role in the evolution of the human neocortex is very exciting,” said Dr. Takahashi, a corresponding author on the new study, Chairman of Neuroscience at UT Southwestern, Investigator for the Howard Hughes Medical Institute, and holder of the Loyd B. Sands Distinguished Chair in Neuroscience.
The Konopka Lab will seek to expand on the findings by studying brain organoids – essentially mini human brains grown in a dish – to understand the specific targets that CLOCK regulates.
The team will manipulate CLOCK in these tissues and document changes in function, such as defects in neuronal migration or the development of other cell types. Dr. Konopka’s research will also involve “humanized mice,” which have been given a boost of CLOCK in their neocortex. The lab will monitor for various changes in brain development and behavior.
“There is so much we don’t know about human brain development and evolution,” said Dr. Konopka, Associate Professor of Neuroscience and the Jon Heighten Scholar in Autism Research. “We’re putting more pieces of the puzzle together to understand which genes are connected to others.”
Funding: The study was supported with grants from the National Institute of Mental Health.
Source: Rachel Griess – UT Southwestern Medical Center
Publisher: Organized by NeuroscienceNews.com.
Image Source: NeuroscienceNews.com image is credited to UT Southwestern Medical Center.
Original Research: Abstract for “Novel transcriptional networks regulated by CLOCK in human neurons” by Miles R. Fontenot, Stefano Berto, Yuxiang Liu, Gordon Werthmann, Connor Douglas, Noriyoshi Usui, Kelly Gleason, Carol A. Tamminga, Joseph S. Takahashi, and Genevieve Konopka in Genes & Development. Published online December 1 2017 doi:10.1101/gad.305813.117
Novel transcriptional networks regulated by CLOCK in human neurons
The molecular mechanisms underlying human brain evolution are not fully understood; however, previous work suggested that expression of the transcription factor CLOCK in the human cortex might be relevant to human cognition and disease. In this study, we investigated this novel transcriptional role for CLOCK in human neurons by performing chromatin immunoprecipitation sequencing for endogenous CLOCK in adult neocortices and RNA sequencing following CLOCK knockdown in differentiated human neurons in vitro. These data suggested that CLOCK regulates the expression of genes involved in neuronal migration, and a functional assay showed that CLOCK knockdown increased neuronal migratory distance. Furthermore, dysregulation of CLOCK disrupts coexpressed networks of genes implicated in neuropsychiatric disorders, and the expression of these networks is driven by hub genes with human-specific patterns of expression. These data support a role for CLOCK-regulated transcriptional cascades involved in human brain evolution and function.
“Novel transcriptional networks regulated by CLOCK in human neurons” by Miles R. Fontenot, Stefano Berto, Yuxiang Liu, Gordon Werthmann, Connor Douglas, Noriyoshi Usui, Kelly Gleason, Carol A. Tamminga, Joseph S. Takahashi, and Genevieve Konopka in Genes & Development. Published online December 1 2017 doi:10.1101/gad.305813.117