5 research outputs found
Integrative functional genomic analysis of human brain development and neuropsychiatric risks
To broaden our understanding of human neurodevelopment, we profiled transcriptomic and epigenomic landscapes across brain regions and/or cell types for the entire span of prenatal and postnatal development. Integrative analysis revealed temporal, regional, sex, and cell type-specific dynamics.We observed a global transcriptomic cup-shaped pattern, characterized by a late fetal transition associated with sharply decreased regional differences and changes in cellular composition and maturation, followed by a reversal in childhood-adolescence, and accompanied by epigenomic reorganizations. Analysis of gene coexpression modules revealed relationships with epigenomic regulation and neurodevelopmental processes. Genes with genetic associations to brain-based traits and neuropsychiatric disorders (including MEF2C, SATB2, SOX5, TCF4, and TSHZ3) converged in a small number of modules and distinct cell types, revealing insights into neurodevelopment and the genomic basis of neuropsychiatric risks
Supplementary Material for: Transcriptional Gene Silencing of the Autism-Associated Long Noncoding RNA MSNP1AS in Human Neural Progenitor Cells
<p>The long noncoding RNA <i>MSNP1AS</i> (moesin pseudogene 1,
antisense) is a functional element that was previously associated with
autism spectrum disorder (ASD) with genome-wide significance. Expression
of <i>MSNP1AS</i> was increased 12-fold in the cerebral cortex of
individuals with ASD and 22-fold in individuals with a genome-wide
significantly associated ASD genetic marker on chromosome 5p14.1.
Overexpression of <i>MSNP1AS</i> in human neuronal cells caused
decreased expression of moesin protein, which is involved in neuronal
process stability. In this study, we hypothesize that <i>MSNP1AS</i>
knockdown impacts global transcriptome levels. We transfected the human
neural progenitor cell line SK- N-SH with constructs that caused a 50%
suppression of <i>MSNP1AS</i> expression. After 24 h, cells were
harvested for total RNA isolation. Strand-specific RNA sequencing
analysis indicated altered expression of 1,352 genes, including altered
expression of 318 genes following correction for multiple comparisons.
Expression of the <i>OAS2</i> gene was increased >150-fold, a result
that was validated by quantitative PCR. Gene ontology analysis of the
318 genes with altered expression following correction for multiple
comparisons indicated that upregulated genes were significantly enriched
for genes involved in immune response, and downregulated genes were
significantly enriched for genes involved in chromatin remodeling. These
data indicate multiple transcriptional and translational functions of <i>MSNP1AS</i>
that impact ASD-relevant biological processes. Chromatin remodeling and
immune response are biological processes implicated by genes with rare
mutations associated with ASD. Our data suggest that the functional
elements implicated by association of common genetic variants impact the
same biological processes, suggesting a possible shared common
molecular pathway of ASD.</p