University of Massachusetts Medical School Faculty Publications
UMMS Affiliation
Brudnick Neuropsychiatric Research Institute, Department of Psychiatry; Program in Bioinformatics and Integrative Biology
Publication Date
4-11-2013
Document Type
Article
Disciplines
Bioinformatics | Computational Neuroscience | Developmental Biology | Genetics and Genomics | Molecular and Cellular Neuroscience | Molecular Genetics | Neuroscience and Neurobiology
Abstract
Development of prefrontal and other higher-order association cortices is associated with widespread changes in the cortical transcriptome, particularly during the transitions from prenatal to postnatal development, and from early infancy to later stages of childhood and early adulthood. However, the timing and longitudinal trajectories of neuronal gene expression programs during these periods remain unclear in part because of confounding effects of concomitantly occurring shifts in neuron-to-glia ratios. Here, we used cell type-specific chromatin sorting techniques for genome-wide profiling of a histone mark associated with transcriptional regulation--H3 with trimethylated lysine 4 (H3K4me3)--in neuronal chromatin from 31 subjects from the late gestational period to 80 years of age. H3K4me3 landscapes of prefrontal neurons were developmentally regulated at 1,157 loci, including 768 loci that were proximal to transcription start sites. Multiple algorithms consistently revealed that the overwhelming majority and perhaps all of developmentally regulated H3K4me3 peaks were on a unidirectional trajectory defined by either rapid gain or loss of histone methylation during the late prenatal period and the first year after birth, followed by similar changes but with progressively slower kinetics during early and later childhood and only minimal changes later in life. Developmentally downregulated H3K4me3 peaks in prefrontal neurons were enriched for Paired box (Pax) and multiple Signal Transducer and Activator of Transcription (STAT) motifs, which are known to promote glial differentiation. In contrast, H3K4me3 peaks subject to a progressive increase in maturing prefrontal neurons were enriched for activating protein-1 (AP-1) recognition elements that are commonly associated with activity-dependent regulation of neuronal gene expression. We uncovered a developmental program governing the remodeling of neuronal histone methylation landscapes in the prefrontal cortex from the late prenatal period to early adolescence, which is linked to cis-regulatory sequences around transcription start sites.
Rights and Permissions
Copyright: 2013 Shulha et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
DOI of Published Version
10.1371/journal.pgen.1003433
Source
PLoS Genet. 2013 Apr;9(4):e1003433. doi: 10.1371/journal.pgen.1003433. Link to article on publisher's site
Related Resources
Journal/Book/Conference Title
PLoS genetics
PubMed ID
23593028
Repository Citation
Shulha, Hennady P.; Cheung, Iris; Guo, Yin; Akbarian, Schahram; and Weng, Zhiping, "Coordinated cell type-specific epigenetic remodeling in prefrontal cortex begins before birth and continues into early adulthood" (2013). University of Massachusetts Medical School Faculty Publications. 126.
https://escholarship.umassmed.edu/faculty_pubs/126
Included in
Bioinformatics Commons, Computational Neuroscience Commons, Developmental Biology Commons, Molecular and Cellular Neuroscience Commons, Molecular Genetics Commons