ChIP-seq analysis of Foxa2 binding sites in midbrain dopaminergic progenitors
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ABSTRACT:
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| ERR126309.fastq.gz | Fastqsanger.gz | |||
| ERR126310.fastq.gz | Fastqsanger.gz | |||
| ERR126311.fastq.gz | Fastqsanger.gz | |||
| ERR126312.fastq.gz | Fastqsanger.gz |
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Project description:Embryonic stem (ES) cells were differentiated in culture to midbrain dopaminergic (mDA) progenitors and subjected to ChIP-seq analysis to resolve genome-wide binding sites of forkhead box protein A2 (Foxa2). Foxa2 was found to directly regulate multiple lineage pathways to specify midbrain dopaminergic and floor plate progenitor identity.
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Project description:Ventral midbrain (VM) dopaminergic progenitor cells derived from human pluripotent stem cells have the potential to replace endogenously lost dopamine neurons and are currently in preclinical and clinical development for treatment of Parkinson’s Disease (PD). However, one main challenge in the quality control of the cells is that rostral and caudal VM progenitors are extremely similar transcriptionally though only the caudal VM cells give rise to dopaminergic neurons with functionality in PD. Therefore, it is critical to develop assays which can rapidly and reliably discriminate rostral from caudal VM cells during clinical manufacturing. Here, we applied shotgun proteomics to search for novel secreted biomarkers specific for caudal VM progenitors compared to rostral VM progenitors and validated key hits by ELISA. From this, we identified novel secreted markers (CPE, LGI1 and PDGFC) significantly enriched in caudal versus rostral VM progenitor cultures, whereas the markers CNTN2 and CORIN were significantly enriched in rostral VM cultures. With this data, we suggest and test in clinical grade samples a panel of coupled ELISA assays that can be applied as a quality control tool for assessing the correct patterning of cells during clinical manufacturing.
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Project description:Despite the progress in safety and efficacy of cell therapy with pluripotent stem cells (PSCs), the presence of residual undifferentiated stem cells or proliferating neural progenitor cells (NPCs) with rostral identity has remained a major challenge. Here we reported the generation of an LMX1A knock-in GFP reporter human embryonic stem cell (hESC) line that marks the early dopaminergic progenitors during neural differentiation. Purified GFP positive cells in vitro exhibited expression of mRNA and proteins that characterized and matched the midbrain dopaminergic identity. Further proteomic analysis of enriched LMX1A+ cells identified several membrane associated proteins including CNTN2, enabling prospective isolation of LMX1A+ progenitor cells. Transplantation of hPSC-derived purified CNTN2+ progenitors enhanced dopamine release from transplanted cells in the host brain and alleviated Parkinson’s disease symptoms in animal models. Our study establishes an efficient approach for purification of large numbers of hPSC-derived dopaminergic progenitors for therapeutic applications.
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Project description:E12.5 wild-type embryos were dissected to collect ventral midbrain regions. Samples were crosslinked 10min with 1% formaldehyde and processed for chromatin extraction and Chromatin Immunoprecipitation (ChIP) following the Millipore upstate protocol. Libraries were prepared using the illumina ChIP-Seq DNA Sample Prep Kit. ChIP-Seq libraries were sequenced on the Illumina GAIIx.
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Project description:Neuronal differentiation relies on tightly regulated transcriptional programs driven by morphogens, yet the role of physiologically derived metabolites in development remains poorly understood. Here, we investigated the effect of the ketone body β-hydroxybutyrate on dopaminergic differentiation using midbrain organoids derived from human embryonic stem cells. Treatment with 1 mM β-hydroxybutyrate for 16 days significantly increased the number of TH⁺ dopaminergic neurons. Transcriptomic analysis by RNA-seq at days 8 and 16 revealed the enrichment of neuronal and dopamine-associated genes, while CUT&RUN profiling of H3K27ac uncovered widespread epigenomic remodeling at neural and dopaminergic regulatory regions. Motif and clustering analyses identified stage-specific enhancer groups, including a day 16-enriched cluster containing validated GeneHancer elements with predicted LMX1B and FOXA2 binding sites. Integration of predicting transcriptional factor binding motifs, and RNAseq data and enrichment H3K27ac enabled the construction of gene regulatory networks using our custom web platform, Enhancer Network Explorer. Together, our results demonstrate that β-hydroxybutyrate reshapes the epigenomic landscape to promote dopaminergic differentiation, suggesting that ketone bodies plays a role in human brain development.
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Project description:Human induced pluripotent stem cells (iPSCs) can provide a promising source of midbrain dopaminergic (mDA) neurons for cell replacement therapy for Parkinson's disease (PD). However, iPSC-derived donor cells inevitably contain tumorigenic or inappropriate cells. To eliminate these unwanted cells, cell sorting using antibodies for specific markers such as CORIN or ALCAM have been developed, but neither marker is specific for ventral midbrain. Here, we employed a double-selection strategy for cells expressing both CORIN and LMX1A::GFP and report a novel cell surface marker to enrich mDA progenitors, LRTM1. When transplanted into 6-OHDA-lesioned rats, human iPSC-derived LRTM1+ cells survived and differentiated into mDA neurons in vivo, resulting in significant improvement in motor behavior without tumor formation. In addition, LRTM1+ cells exhibited efficient survival of mDA neurons in the brain of an MPTP-treated monkey. Thus, LRTM1 can provide a powerful tool for efficient and safe cell therapy for PD patients.
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