Epigenomic and chromosomal architectural reconfiguration in developing human frontal cortex and hippocampus

The human frontal cortex and hippocampus play critical roles in learning and cognition. We investigated the epigenomic and 3D chromatin conformational reorganization during the development of the frontal cortex and hippocampus, using more than 53,000 joint single-nucleus profiles of chromatin conformation and DNA methylation (sn-m3C-seq). The remodeling of DNA methylation predominantly occurs during late-gestational to early-infant development and is temporally separated from chromatin conformation dynamics. Neurons have a unique Domain-Dominant chromatin conformation that is different from the Compartment-Dominant conformation of glial cells and non-brain tissues. We reconstructed the regulatory programs of cell-type differentiation and found putatively causal common variants for schizophrenia strongly overlap with chromatin loop-connected, cell-type-specific regulatory regions. Our data demonstrate that single-cell 3D-regulome is an effective approach for dissecting neuropsychiatric risk loci.

[1]  C. Cadwell,et al.  Fate mapping of neural stem cell niches reveals distinct origins of human cortical astrocytes , 2022, Science.

[2]  Jesse R. Dixon,et al.  Single nucleus multi-omics identifies human cortical cell regulatory genome diversity , 2022, Cell genomics.

[3]  Pawel F. Przytycki,et al.  Single-cell epigenomics reveals mechanisms of human cortical development , 2021, Nature.

[4]  Taylor M. Lagler,et al.  SnapHiC: a computational pipeline to identify chromatin loops from single-cell Hi-C data , 2021, Nature Methods.

[5]  X. Xie,et al.  Changes in genome architecture and transcriptional dynamics progress independently of sensory experience during post-natal brain development , 2021, Cell.

[6]  Kyle J. Gaulton,et al.  An atlas of gene regulatory elements in adult mouse cerebrum , 2020, Nature.

[7]  Harrison W. Gabel,et al.  Emerging Insights into the Distinctive Neuronal Methylome. , 2020, Trends in genetics : TIG.

[8]  Harrison W. Gabel,et al.  DNMT3A Haploinsufficiency Results in Behavioral Deficits and Global Epigenomic Dysregulation Shared across Neurodevelopmental Disorders , 2020, bioRxiv.

[9]  Aviv Regev,et al.  Chromatin Potential Identified by Shared Single-Cell Profiling of RNA and Chromatin , 2020, Cell.

[10]  Jennifer E. Phillips-Cremins,et al.  Three-dimensional genome restructuring across timescales of activity-induced neuronal gene expression , 2020, Nature Neuroscience.

[11]  Jesse R. Dixon,et al.  DNA methylation atlas of the mouse brain at single-cell resolution , 2020, Nature.

[12]  H. Zoghbi,et al.  Losing Dnmt3a dependent methylation in inhibitory neurons impairs neural function by a mechanism impacting Rett syndrome , 2020, eLife.

[13]  Christopher D. Brown,et al.  The GTEx Consortium atlas of genetic regulatory effects across human tissues , 2019, Science.

[14]  Kerstin B. Meyer,et al.  BBKNN: fast batch alignment of single cell transcriptomes , 2019, Bioinform..

[15]  Harrison W. Gabel,et al.  MeCP2 Represses Enhancers through Chromosome Topology-Associated DNA Methylation. , 2019, Molecular cell.

[16]  Matthew G. Keefe,et al.  Development and Arealization of the Cerebral Cortex , 2019, Neuron.

[17]  Conor Fitzpatrick,et al.  Simultaneous profiling of 3D genome structure and DNA methylation in single human cells , 2019, Nature Methods.

[18]  Jianzhu Ma,et al.  Robust single-cell Hi-C clustering by convolution- and random-walk–based imputation , 2019, Proceedings of the National Academy of Sciences.

[19]  T. Holy,et al.  Sensory Experience Remodels Genome Architecture in Neural Circuit to Drive Motor Learning , 2019, Nature.

[20]  Fabian J Theis,et al.  PAGA: graph abstraction reconciles clustering with trajectory inference through a topology preserving map of single cells , 2019, Genome biology.

[21]  Stephan J Sanders,et al.  Integrative functional genomic analysis of human brain development and neuropsychiatric risks , 2018, Science.

[22]  Fan Zhang,et al.  Fast, sensitive, and accurate integration of single cell data with Harmony , 2018, bioRxiv.

[23]  Michael E. Greenberg,et al.  Activity-Regulated Transcription: Bridging the Gap between Neural Activity and Behavior , 2018, Neuron.

[24]  P. Donnelly,et al.  The UK Biobank resource with deep phenotyping and genomic data , 2018, Nature.

[25]  J. Ecker,et al.  Dynamic DNA methylation: In the right place at the right time , 2018, Science.

[26]  Justin P Sandoval,et al.  Robust single-cell DNA methylome profiling with snmC-seq2 , 2018, Nature Communications.

[27]  Howard Y. Chang,et al.  Global DNA methylation remodeling during direct reprogramming of fibroblasts to neurons , 2018, bioRxiv.

[28]  Fabian J Theis,et al.  SCANPY: large-scale single-cell gene expression data analysis , 2018, Genome Biology.

[29]  G. Miyoshi,et al.  Hierarchical genetic interactions between FOXG1 and LHX2 regulate the formation of the cortical hem in the developing telencephalon , 2018, Development.

[30]  Harrison W. Gabel,et al.  Early-Life Gene Expression in Neurons Modulates Lasting Epigenetic States , 2017, Cell.

[31]  N. Heintz,et al.  5-hydroxymethylcytosine accumulation in postmitotic neurons results in functional demethylation of expressed genes , 2017, Proceedings of the National Academy of Sciences.

[32]  Justin P Sandoval,et al.  Single-cell methylomes identify neuronal subtypes and regulatory elements in mammalian cortex , 2017, Science.

[33]  Evan Z. Macosko,et al.  Heritability enrichment of specifically expressed genes identifies disease-relevant tissues and cell types , 2017, Nature Genetics.

[34]  Joseph R Ecker,et al.  Cerebral Organoids Recapitulate Epigenomic Signatures of the Human Fetal Brain. , 2016, Cell reports.

[35]  Anthony D. Schmitt,et al.  A Compendium of Chromatin Contact Maps Reveals Spatially Active Regions in the Human Genome. , 2016, Cell reports.

[36]  Jesse R. Dixon,et al.  Chromatin Domains: The Unit of Chromosome Organization. , 2016, Molecular cell.

[37]  N. Šestan,et al.  The Cellular and Molecular Landscapes of the Developing Human Central Nervous System , 2016, Neuron.

[38]  Yakir A Reshef,et al.  Partitioning heritability by functional annotation using genome-wide association summary statistics , 2015, Nature Genetics.

[39]  Matthew D. Schultz,et al.  Human Body Epigenome Maps Reveal Noncanonical DNA Methylation Variation , 2015, Nature.

[40]  Wei Li,et al.  MeCP2 binds to non-CG methylated DNA as neurons mature, influencing transcription and the timing of onset for Rett syndrome , 2015, Proceedings of the National Academy of Sciences.

[41]  Harrison W. Gabel,et al.  Disruption of DNA methylation-dependent long gene repression in Rett syndrome , 2015, Nature.

[42]  M. Jacomy,et al.  ForceAtlas2, a Continuous Graph Layout Algorithm for Handy Network Visualization Designed for the Gephi Software , 2014, PloS one.

[43]  Matthew D. Schultz,et al.  Global Epigenomic Reconfiguration During Mammalian Brain Development , 2013, Science.

[44]  Vijay K. Tiwari,et al.  DNA-binding factors shape the mouse methylome at distal regulatory regions , 2011, Nature.

[45]  J. Kleinman,et al.  Spatiotemporal transcriptome of the human brain , 2011, Nature.

[46]  William Stafford Noble,et al.  FIMO: scanning for occurrences of a given motif , 2011, Bioinform..

[47]  Mikael Bodén,et al.  MEME Suite: tools for motif discovery and searching , 2009, Nucleic Acids Res..

[48]  P. Arlotta,et al.  Neuronal subtype specification in the cerebral cortex , 2007, Nature Reviews Neuroscience.