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Open chromatin dynamics reveals stage-specific transcriptional networks in hiPSC-based neurodevelopmental model.

ABSTRACT: Chromatin accessibility to transcription factors (TFs) strongly influences gene transcription and cell differentiation. However, a mechanistic understanding of the transcriptional control during the neuronal differentiation of human induced pluripotent stem cells (hiPSCs), a promising cellular model for mental disorders, remains elusive. Here, we carried out additional analyses on our recently published open chromatin regions (OCRs) profiling at different stages of hiPSC neuronal differentiation. We found that the dynamic changes of OCR during neuronal differentiation highlighted cell stage-specific gene networks, and the chromatin accessibility at the core promoter region of a gene correlates with the corresponding transcript abundance. Within the cell stage-specific OCRs, we identified the binding of cell stage-specific TFs and observed a lag of a neuronal TF binding behind the mRNA expression of the corresponding TF. Interestingly, binding footprints of NEUROD1 and NEUROG2, both of which induce high efficient conversion of hiPSCs to glutamatergic neurons, were among those most enriched in the relatively mature neurons. Furthermore, TF network analysis showed that both NEUROD1 and NEUROG2 were present in the same core TF network specific to more mature neurons, suggesting a pivotal mechanism of epigenetic control of neuronal differentiation and maturation. Our study provides novel insights into the epigenetic control of glutamatergic neurogenesis in the context of TF networks, which may be instrumental to improving hiPSC modeling of neuropsychiatric disorders.

SUBMITTER: Zhang S

PROVIDER: S-EPMC6025752 | biostudies-literature | 2018 May

REPOSITORIES: biostudies-literature

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Open chromatin dynamics reveals stage-specific transcriptional networks in hiPSC-based neurodevelopmental model.

Zhang Siwei S Moy Winton W Zhang Hanwen H Leites Catherine C McGowan Heather H Shi Jianxin J Sanders Alan R AR Pang Zhiping P ZP Gejman Pablo V PV Duan Jubao J

Stem cell research 20180331

Chromatin accessibility to transcription factors (TFs) strongly influences gene transcription and cell differentiation. However, a mechanistic understanding of the transcriptional control during the neuronal differentiation of human induced pluripotent stem cells (hiPSCs), a promising cellular model for mental disorders, remains elusive. Here, we carried out additional analyses on our recently published open chromatin regions (OCRs) profiling at different stages of hiPSC neuronal differentiation ...[more]

PMID: 29631039

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Project description:Abstract Background Neuropsychiatric disorders, including schizophrenia (SZ), afflict a significant fraction of the population. Recent genome-wide association studies (GWAS) under the framework of the Psychiatric Genomics Consortium (PGC), along with large-scale sequencing efforts, have identified a plethora of disease risk loci with common and/or rare risk variants. Translating these exciting genomic findings into causation and disease biology offers the promise of developing more tailored therapies in psychiatry. However, understanding the disease biology underlying most GWAS findings remains challenging: (1) The paucity of disease-relevant biological materials for assaying molecular and cellular phenotypes associated with risk loci; (2) Most disease variants lie within poorly-annotated noncoding parts of the genome for which functional interpretation is challenging; and (3) Each locus often contains many genes/variants equivalently associated with the disease due to linkage disequilibrium, and it is difficult to identify which are the likely causal gene/variant. Human neurons derived from induced pluripotent stem cells (iPSCs), both monolayer cultures (2D model) and the emerging brain organoids (3D model), provide a promising alternative to human brains for recapitulating cellular phenotypes relevant to psychiatric disorders. CRISPR/Cas9 editing further strengthens the utility of these models by enabling the generation of isogenic lines with essentially the same genetic background on which allelic effects of a risk variant can be directly compared, thus increasing the sensitivity to detect typically small effects of a GWAS variant. Methods To functionally assess the relevance of noncoding sequences in neuropsychiatric disorders, we hypothesized that disease-relevant noncoding sequences likely overlap with cell-specific open chromatin regions (OCRs). We have carried out a genome-wide OCR profiling of excitatory neuronal differentiation from human iPSCs using an Assay for Transposase-Accessible Chromatin by sequencing (ATAC-seq). Results We found that OCRs in neurons were enriched SZ risk variants in neural OCRs and can help prioritize putatively functional SZ risk variants that may impact OCRs and consequently, cellular development. At a leading SZ-risk locus flanking MIR137, we further examined the functional effects of a prioritized common GWAS SNP rs1198588 in CRISPR/Cas9-edited hiPSCs, and found that SZ-risk allele of rs1198588 altered MIR137 expression, OCR dynamics and dendrite arborization/synapse maturation. To systematically identify such disease risk variants that may affect OCR, we further carried out a proof-of-concept analysis of allele-specific open chromatin (ASoC) of in hIPSC-derived neurons. We found that Heterozygous SNPs showing ASoC are more prevalent in neurons than in hiPSCs. Out of the 12 schizophrenia GWAS-implicated SNPs that we found in neuronal OCRs of this single individual, two SNPs showed ASoC and are thus putatively functional: one lies within the 5’-UTR of CHRNA5 (cholinergic receptor, nicotinic, alpha 5) and the other is in the promoter region of VPS45, a Sec1 family gene involved in synaptic transmission. We are currently in the process of replicating the observed landscape of ASoC in iPSC-derived neurons from a larger sample pool. Discussion Our study suggests that OCR profiling in a human iPSC model of neuron differentiation can predict functional noncoding sequences that regulate neurodevelopment.

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Open chromatin dynamics reveals stage-specific transcriptional networks in hiPSC-based neurodevelopmental model.

Publications

Open chromatin dynamics reveals stage-specific transcriptional networks in hiPSC-based neurodevelopmental model.

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