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Physiological, Morphological and Neurochemical Characterization of Neurons Modulated by Movement
Published on: April 21, 2011
Comparative characterization of human accelerated regions in neurons
Xiekui Cui1, Han Yang1, Charles Cai1
1Institute for Human Genetics, University of California, San Francisco, San Francisco, CA, USA.
Human accelerated regions (HARs) regulate genes crucial for brain development. These HARs show species-specific functions, impacting human neuron evolution and gene expression.
Area of Science:
- Genomics
- Evolutionary Biology
- Neuroscience
Background:
- Human accelerated regions (HARs) are conserved genomic regions with rapid substitutions after human-chimpanzee divergence.
- HARs are near neurodevelopmental genes, suggesting regulatory roles, but their targets and functions are unclear.
Purpose of the Study:
- To investigate the cis-regulatory functions of HARs in human and chimpanzee neurons.
- To understand HAR contributions to human brain evolution and gene regulation.
Main Methods:
- Prioritized 20 HARs and orthologues using genomic and chromatin looping data.
- Functional characterization via single-cell CRISPR interference in human and chimpanzee iPS cell-derived neurons.
- Prime editing used to assess enhancer activity of HAR variants.
Main Results:
- Demonstrated species-specific gene regulatory functions of HARs.
- HAR202 alters NPAS3 expression by changing transcription factor binding.
- 2xHAR.319 upregulates PUM2, maintaining pluripotency and neuronal differentiation.
- HAR26;2xHAR.178 variants show differential enhancer activity, with one linked to elevated SOCS2 and increased neurite outgrowth.
Conclusions:
- HARs have diverse cis-regulatory functions in human neurons.
- These functions potentially contribute to human brain evolution.
- Revealed endogenous gene regulatory roles of HARs in neuronal development.
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