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Temporal Dynamics and Genetic Control of Transcription in the Human Prefrontal Cortex

ABSTRACT: In order to gain a global molecular perspective on how the human genome gives rise to the brain, we explore the temporal dynamics and genetic control of transcription in human dorsolateral prefrontal cortex in an extensive series of brain tissue from fetal development through aging. We discover a wave of gene expression changes occurring during fetal development which are reversed in early postnatal life. One half century later in life, this phenomenon is mirrored in aging as well as neurodegeneration. While we identify thousands of robust associations of individual genetic polymorphisms with gene expression, we also demonstrate that there is no association between the total extent of genetic differences between subjects and the global similarity of their transcriptional profiles. Hence, the human genome produces a consistent molecular architecture in the prefrontal cortex, despite millions of genetic differences across individuals and races. To enable further discovery, this entire dataset is freely available (GEO). The gene expression from this study can be interrogated gene-by-gene with a biologist-friendly web application available at http://braincloud.jhmi.edu/plots/.

ORGANISM(S): Homo sapiens

PROVIDER: GSE30272 | GEO | 2011/10/27

SECONDARY ACCESSION(S): PRJNA143735

REPOSITORIES: GEO

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Temporal Dynamics and Genetic Control of Transcription in the Human Prefrontal Cortex

Project description:In order to gain a global molecular perspective on how the human genome gives rise to the brain, we explore the temporal dynamics and genetic control of transcription in human dorsolateral prefrontal cortex in an extensive series of brain tissue from fetal development through aging. We discover a wave of gene expression changes occurring during fetal development which are reversed in early postnatal life. One half century later in life, this phenomenon is mirrored in aging as well as neurodegeneration. While we identify thousands of robust associations of individual genetic polymorphisms with gene expression, we also demonstrate that there is no association between the total extent of genetic differences between subjects and the global similarity of their transcriptional profiles. Hence, the human genome produces a consistent molecular architecture in the prefrontal cortex, despite millions of genetic differences across individuals and races. To enable further discovery, this entire dataset is freely available (GEO). RNA from 269 human prefrontal cortex samples ranging from fetal development (negative ages) through aging (80 years) were analyzed on custom 2-color microarrays from the National Human Genome Research Institute (NHGRI) microarray core facility using a reference RNA comprised of a pool of all samples. SNP genotype data for these subjects can be found in dbGAP under Study ID *phs000417.v1.p1* http://www.ncbi.nlm.nih.gov/projects/gap/cgi-bin/study.cgi?study_id=phs000417.v1.p1 Both the gene expression and SNP data from this study can be interrogated gene-by-gene with a biologist-friendly stand-alone application available at http://www.libd.org/braincloud . The original publication of this data appeared in the Oct. 27th 2011 volume of Nature: http://www.nature.com/nature/journal/v478/n7370/full/nature10524.html .

2011-10-26 | E-GEOD-30272 | biostudies-arrayexpress

Gene expression data from primate postnatal brain in prefrontal cortex: time course

Project description:Gene expression changes determine functional differentiation during development and are associated with functional decline during aging. While developmental changes are tightly regulated, regulation of aging changes is not well established. To assess the regulatory basis of age-related changes and investigate the mechanism of regulatory transition between development and aging, we measured mRNA and microRNA expression patterns in brains (superior frontal gyrus) of humans and rhesus macaques over the entire speciesâ lifespan. We find that in both species, developmental and aging changes overlap in the course of lifetime with many changes found at the late age initiating in early childhood. Human post-mortem brain samples from the superior frontal gyrus region of the prefrontal cortex were collected. The age ranges of the indibiual in human covered its whole life span fom newborn to death. RNA extracted from the dissected tissue was hybridized to AffymetrixÂ® Human Gene 1.0 ST arrays. Rhesus macaque post-mortem brain samples from the superior frontal gyrus region of the prefrontal cortex were collected. The age ranges of the indibiual in rhesus macaque covered the whole life span fom newborn to death. RNA extracted from the dissected tissue was hybridized to AffymetrixÂ® Human Gene 1.0 ST arrays.

2010-06-24 | E-GEOD-17757 | biostudies-arrayexpress

Early-life prefrontal cortex inhibition and early-life stress lead to long-lasting behavioral, transcriptional, and physiological impairments

Project description:Early-life stress has been linked to multiple neurodevelopmental and neuropsychiatric deficits. Our previous studies have linked maternal presence/absence from the nest in developing rat pups to changes in prefrontal cortex activity. Furthermore, we have shown that these changes are modulated by serotonergic signaling. Here we test whether changes in prefrontal cortex activity during early-life affect the developing cortex leading to behavioral alterations in the adult. We show that inhibiting the prefrontal cortex of mouse pups leads to cognitive deficits in the adult comparable to those seen following maternal separation. Moreover, we show that activating the prefrontal cortex during maternal separation can prevent these behavioral deficits. To test how maternal separation affects the transcriptional profile of the prefrontal cortex we performed single-nucleus RNA sequencing. Maternal separation lead to differential gene expression almost exclusively in inhibitory neurons. Among others, we found changes in GABAergic and serotonergic pathways in these interneurons. Interestingly, both maternal separation and early-life prefrontal cortex inhibition led to changes in physiological responses in prefrontal activity to GABAergic and serotonergic antagonists that were similar to the responses of more immature brains. Prefrontal activation during maternal separation prevented these changes. These data point to a crucial role of prefrontal cortex activity during early-life in behavioral expression in adulthood

2024-03-14 | GSE254342 | GEO

BrainCloud: Data from Human Postmortem Brain Across the Lifespan

Project description:<p>This study explores the temporal dynamics and genetic control of transcription and DNA methylation in the human dorsolateral prefrontal cortex in postmortem tissue. This study examines 269 subjects for gene expression (version 1) and 108 subjects for DNA methylation (version 2). The subjects are normal controls without neuropathological and neuropsychiatric diagnosis and range in age from fetal weeks 14-20 through old age (>80). We discover fast changes in gene expression occurring during early brain development. Later in life, the changes are considerably slower. Many genes reverse pattern of expression between fetal and early postnatal development. We identify thousands of strong associations of SNPs with gene expression. We examine DNA methylation in ~14,500 genes at ~27,000 CpG loci focused on 5' promoter regions. The fastest changes in DNA methylation also occur during the prenatal period, slow down markedly after birth and continue to slow further with aging. DNA methylation is strongly associated with genotypic variants and correlates with expression of a subset of genes. DNA for genotyping was obtained from the cerebella and applied to either Illumina 650K or 1 million BeadArrays - only genotypes common to both platforms are analyzed here. Genotypes were called using BeadExpress software. Doi: 10.1038/nature10524 <a href="http://www.ncbi.nlm.nih.gov/pubmed/22031444">Nature</a>, 478:519-524, 2011; doi:10.1016/j.ajhg.2011.12.020, AJHG 90, 1-13, Feb 10, 2012. The methylation data can be downloaded at: <a href="http://BrainCloud.jhmi.edu/downloads.htm">BrainCloud.</a></p>

| phs000417 | dbGaP

A switch from neuronal network development to maintenance during postnatal development of rat prefrontal cortex

Project description:To unravel the gene expression changes during postnatal prefrontal cortex development, RNA-seq was performed in the rat medial prefrontal cortex at five time points from early life to adulthood (postnatal day 8, 14, 21, 35 and 70) and differential expression of protein-coding genes, lincRNAs and alternative exons was analyzed. A switch from neuronal network development to maintenance during postnatal rat prefrontal cortex development was shown.

2017-01-01 | GSE79860 | GEO

miRNA expression data from human postnatal brain in prefrontal cortex: time course

Project description:Gene expression changes determine functional differentiation during development and are associated with functional decline during aging. While developmental changes are tightly regulated, regulation of aging changes is not well established. To assess the regulatory basis of age-related changes and investigate the mechanism of regulatory transition between development and aging, we measured mRNA and microRNA expression patterns in brains of humans and rhesus macaques over the entire species’ lifespan. We find that in both species, developmental and aging changes overlap in the course of lifetime with many changes found at the late age initiating in early childhood. Keywords: miRNA Age Series Keywords: Non-coding RNA profiling by high throughput sequencing Human post-mortem brain samples from the superior frontal gyrus region of the prefrontal cortex were collected. The age ranges of the indibiual in rhesus macaque covered the whole life span fom newborn to death.

2010-06-09 | E-GEOD-18012 | biostudies-arrayexpress

miRNA expression data from rhesus macaque postnatal brain in prefrontal cortex: time course

Project description:Gene expression changes determine functional differentiation during development and are associated with functional decline during aging. While developmental changes are tightly regulated, regulation of aging changes is not well established. To assess the regulatory basis of age-related changes and investigate the mechanism of regulatory transition between development and aging, we measured mRNA and microRNA expression patterns in brains of humans and rhesus macaques over the entire species’ lifespan. We find that in both species, developmental and aging changes overlap in the course of lifetime with many changes found at the late age initiating in early childhood. Keywords: miRNA Age Series Keywords: Non-coding RNA profiling by high throughput sequencing rhesus macaque post-mortem brain samples from the superior frontal gyrus region of the prefrontal cortex were collected. The age ranges of the indibiual in rhesus macaque covered the whole life span fom newborn to death.

2010-06-09 | E-GEOD-18013 | biostudies-arrayexpress

Methylomic profiling of human brain tissue supports a neurodevelopmental origin for schizophrenia.

Project description:Background: Schizophrenia is a severe neuropsychiatric disorder that is hypothesized to result from disturbances in early brain development, and there is mounting evidence to support a role for developmentally-regulated epigenetic variation in the molecular etiology of the disorder. Here, we describe a systematic study of schizophrenia-associated methylomic variation in the adult brain and its relationship to changes in DNA methylation across human fetal brain development. Results: We profile methylomic variation in matched prefrontal cortex and cerebellum brain tissue from schizophrenia patients and controls, identifying disease-associated differential DNA methylation at multiple loci, particularly in the prefrontal cortex, and confirming these differences in an independent set of adult brain samples. Our data reveal discrete modules of co-methylated loci associated with schizophrenia that are enriched for genes involved in neurodevelopmental processes and include loci implicated by genetic studies of the disorder. Methylomic data from human fetal cortex samples, spanning 23 to 184 days post-conception, indicates that disease-associated differentially methylated positions are significantly enriched for loci at which DNA methylation is dynamically altered during human fetal brain development. Conclusions: Our data support the hypothesis that schizophrenia has an important early neurodevelopmental component, and suggest that epigenetic mechanisms may mediate these effects. 33 post-mortem brain (prefrontal cortex) samples (18 schizophrenia cases and 15 controls) were obtained from Douglas Bell-Canada Brain Bank (DBCBB), Montreal, Canada. Bisulfite converted DNA from these samples were hybridised to the Illumina Infinium 450k Human Methylation Beadchip v1.0.

2014-09-13 | E-GEOD-61380 | biostudies-arrayexpress

Methylomic profiling of human brain tissue supports a neurodevelopmental origin for schizophrenia.

Project description:Background: Schizophrenia is a severe neuropsychiatric disorder that is hypothesized to result from disturbances in early brain development, and there is mounting evidence to support a role for developmentally-regulated epigenetic variation in the molecular etiology of the disorder. Here, we describe a systematic study of schizophrenia-associated methylomic variation in the adult brain and its relationship to changes in DNA methylation across human fetal brain development. Results: We profile methylomic variation in matched prefrontal cortex and cerebellum brain tissue from schizophrenia patients and controls, identifying disease-associated differential DNA methylation at multiple loci, particularly in the prefrontal cortex, and confirming these differences in an independent set of adult brain samples. Our data reveal discrete modules of co-methylated loci associated with schizophrenia that are enriched for genes involved in neurodevelopmental processes and include loci implicated by genetic studies of the disorder. Methylomic data from human fetal cortex samples, spanning 23 to 184 days post-conception, indicates that disease-associated differentially methylated positions are significantly enriched for loci at which DNA methylation is dynamically altered during human fetal brain development. Conclusions: Our data support the hypothesis that schizophrenia has an important early neurodevelopmental component, and suggest that epigenetic mechanisms may mediate these effects. Prefrontal cortex (PFC) and cerebellum samples were obtained from 46 brains archived in the London Brain Bank for Neurodegenerative Disorders (LBBND). Of these 22 were schizophrenia cases, ands of the cases 12 were male.

2014-09-18 | E-GEOD-61431 | biostudies-arrayexpress

Single-nucleus RNA sequencing of dorsolateral prefrontal cortex from normal, pathological aging, and Alzheimer’s disease human brains

Project description:We performed single-nucleus RNA sequencing of the dorsolateral prefrontal cortex from 15 normal, pathological aging, and Alzheimer’s disease human brains that varied by APOE and TREM2 genotype to analyze cell-type specific transcriptomic changes across the range of Alzheimer’s disease pathology and genetic risk factors.

2023-10-02 | GSE243292 | GEO

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