Human-Specific Transcriptional Networks in the Brain

Department of Neurology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA.
Neuron (Impact Factor: 15.05). 08/2012; 75(4):601-17. DOI: 10.1016/j.neuron.2012.05.034
Source: PubMed


Understanding human-specific patterns of brain gene expression and regulation can provide key insights into human brain evolution and speciation. Here, we use next-generation sequencing, and Illumina and Affymetrix microarray platforms, to compare the transcriptome of human, chimpanzee, and macaque telencephalon. Our analysis reveals a predominance of genes differentially expressed within human frontal lobe and a striking increase in transcriptional complexity specific to the human lineage in the frontal lobe. In contrast, caudate nucleus gene expression is highly conserved. We also identify gene coexpression signatures related to either neuronal processes or neuropsychiatric diseases, including a human-specific module with CLOCK as its hub gene and another module enriched for neuronal morphological processes and genes coexpressed with FOXP2, a gene important for language evolution. These data demonstrate that transcriptional networks have undergone evolutionary remodeling even within a given brain region, providing a window through which to view the foundation of uniquely human cognitive capacities.

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    • "Although the composition of the post-synaptic density is well conserved among mammals (Bayés et al., 2010), the dynamic component of plasticity provided by mRNA and miRNA is quite divergent. Human transcription networks have evolved a complexity that drives species-specific gene expression in the pre-frontal (PFC) and frontal cortices (Konopka et al., 2012). "
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    ABSTRACT: The SH-SY5Y culture system is a convenient neuronal model with the potential to elaborate human/primate-specific transcription networks and pathways related to human cognitive disorders. While this system allows for the exploration of specialized features in the human genome, there is still significant debate about how this model should be implemented, and its appropriateness for answering complex functional questions related to human neural architecture. In view of these questions we sought to characterize the posttranscriptional regulatory structure of the two-stage ATRA differentiation, BDNF maturation protocol proposed by Encinas et al. (2000) using integrative whole-genome gene and microRNA (miRNA) expression analysis. We report that ATRA-BDNF induced significant increases in expression of key synaptic genes, brain-specific miRNA and miRNA biogenesis machinery, and in AChE activity, compared with ATRA alone. Functional annotation clustering associated BDNF more significantly with neuronal terms, and with synaptic terms not found in ATRA-only clusters. While our results support use of SH-SY5Y as a neuronal model, we advocate considered selection of the differentiation agent/s relative to the system being modeled.
    Frontiers in Cellular Neuroscience 10/2014; 8. DOI:10.3389/fncel.2014.00325 · 4.29 Impact Factor
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    • "Recent monumental attempts to decipher the transcriptome in the human brain have undoubtedly contributed to our anatomical understanding of the transcriptional network and disease-related changes in inaccessible tissues [4, 5]. Subsequent proteomic or metabolomic analyses will provide further crucial information in the near future. "
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    ABSTRACT: Compared with biochemical information available about the diseases in the central nervous system, that for peripheral neuropathy is quite limited primarily due to the difficulties in obtaining samples. Characterization of the core pathology is a prerequisite to the development of personalized medicine for genetically heterogeneous diseases, such as hereditary motor and sensory neuropathy (HMSN). Here, we first documented the transcriptome profile of distal sural nerve obtained from HMSN patients. RNA-seq analysis revealed that over 12,000 genes are expressed in distal sural nerve. Among them 4,000 transcripts are novel and 10 fusion genes per sample were observed. Comparing dataset from whole exome sequencing revealed that over 1,500 transcriptional base modifications occur during transcription. These data implicate that dynamic alterations are generated when genetic information are transitioned in distal sural nerve. Although, we could not find significant alterations associated with HMSN, these data might provide crucial information about the pathophysiology of HMSN. Therefore, next step in the development of therapeutic strategy for HMSN might be unveiling biochemical and biophysical abnormalities derived from those potent variation.
    06/2014; 23(2):169-72. DOI:10.5607/en.2014.23.2.169
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    • "Constructing bridge theories becomes more difficult because we must unravel regulatory networks not directly " wired " to phenotypes. Konopka et al. (2012) have begun unraveling this structure by a functional, modular analysis of the human vs. nonhuman primate transcriptome , but much remains unknown. Further, language is not like the examples of body plan segmentation or eye formation where functional and developmental processes are well understood in numerous species, both closely and distantly related. "
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    ABSTRACT: Understanding the evolution of language requires evidence regarding origins and processes that led to change. In the last 40 years, there has been an explosion of research on this problem as well as a sense that considerable progress has been made. We argue instead that the richness of ideas is accompanied by a poverty of evidence, with essentially no explanation of how and why our linguistic computations and representations evolved. We show that, to date, (1) studies of nonhuman animals provide virtually no relevant parallels to human linguistic communication, and none to the underlying biological capacity; (2) the fossil and archaeological evidence does not inform our understanding of the computations and representations of our earliest ancestors, leaving details of origins and selective pressure unresolved; (3) our understanding of the genetics of language is so impoverished that there is little hope of connecting genes to linguistic processes any time soon; (4) all modeling attempts have made unfounded assumptions, and have provided no empirical tests, thus leaving any insights into language's origins unverifiable. Based on the current state of evidence, we submit that the most fundamental questions about the origins and evolution of our linguistic capacity remain as mysterious as ever, with considerable uncertainty about the discovery of either relevant or conclusive evidence that can adjudicate among the many open hypotheses. We conclude by presenting some suggestions about possible paths forward.
    Frontiers in Psychology 05/2014; 5:401. DOI:10.3389/fpsyg.2014.00401 · 2.80 Impact Factor
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