PsychENCODE and beyond: transcriptomics and epigenomics of brain development and organoids

Jourdon, Alexandre; Scuderi, Soraya; Capauto, Davide; Abyzov, Alexej; Vaccarino, Flora M.

doi:10.1038/s41386-020-0763-3

Cited by 19 publications

(16 citation statements)

References 179 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Thus, 3D stem cell derived methodologies provide access to a limitless supply of human-derived tissue which can be used to dissect complex diseases defined by “ daunting polygenicity ” [ 10 ] under controlled laboratory conditions [ 11 ]. Cerebral organoids mimic trimester 1 of early brain development and putatively recapitulate the epigenetic [ 12 ], transcriptomic [ 13 , 14 ], and proteomic [ 1 , 11 ] architecture that is expected of the developing mammalian brain. This also includes the recapitulation of cortical cell-type diversity and cellular events such as migration [ 15 ] and evolutionary mechanisms that support neocortical neurogenesis [ 16 ].…”

Section: Introductionmentioning

confidence: 99%

The proteomic architecture of schizophrenia iPSC-derived cerebral organoids reveals alterations in GWAS and neuronal development factors

et al. 2021

View full text Add to dashboard Cite

Schizophrenia (Scz) is a brain disorder that has a typical onset in early adulthood but otherwise maintains unknown disease origins. Unfortunately, little progress has been made in understanding the molecular mechanisms underlying neurodevelopment of Scz due to ethical and technical limitations in accessing developing human brain tissue. To overcome this challenge, we have previously utilized patient-derived Induced Pluripotent Stem Cells (iPSCs) to generate self-developing, self-maturating, and self-organizing 3D brain-like tissue known as cerebral organoids. As a continuation of this prior work, here we provide an architectural map of the developing Scz organoid proteome. Utilizing iPSCs from n = 25 human donors (n = 8 healthy Ctrl donors, and n = 17 Scz patients), we generated 3D cerebral organoids, employed 16-plex isobaric sample-barcoding chemistry, and simultaneously subjected samples to comprehensive high-throughput liquid-chromatography/mass-spectrometry (LC/MS) quantitative proteomics. Of 3,705 proteins identified by high-throughput proteomic profiling, we identified that just ~2.62% of the organoid global proteomic landscape was differentially regulated in Scz organoids. In sum, just 43 proteins were up-regulated and 54 were down-regulated in Scz patient-derived organoids. Notably, a range of neuronal factors were depleted in Scz organoids (e.g., MAP2, TUBB3, SV2A, GAP43, CRABP1, NCAM1 etc.). Based on global enrichment analysis, alterations in key pathways that regulate nervous system development (e.g., axonogenesis, axon development, axon guidance, morphogenesis pathways regulating neuronal differentiation, as well as substantia nigra development) were perturbed in Scz patient-derived organoids. We also identified prominent alterations in two novel GWAS factors, Pleiotrophin (PTN) and Podocalyxin (PODXL), in Scz organoids. In sum, this work serves as both a report and a resource that researchers can leverage to compare, contrast, or orthogonally validate Scz factors and pathways identified in observational clinical studies and other model systems.

show abstract

Section: Introductionmentioning

confidence: 99%

The proteomic architecture of schizophrenia iPSC-derived cerebral organoids reveals alterations in GWAS and neuronal development factors

et al. 2021

View full text Add to dashboard Cite

show abstract

“…Organoids are 3D cultures that realize the self-organizing potential of stem cells 11,12 . Several transcriptome analyses have shown that organoids can recapitulate a variety of early developmental processes in human organs, such as brain 13–17 , retina 18 , kidney 19 , intestinal epithelium 20 , and trophoblast 21 . As chondrogenic tissue formation occurs at the highest levels during fetal/younger stages of life 22 , 3D organoid systems have a unique advantage in achieving in vitro chondrogenesis and even associated organization of extracellular matrices.…”

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Self-organized emergence of hyaline cartilage in hiPSC-derived multi-tissue organoids

Abrahante

Vegoe

et al. 2021

Preprint

View full text Add to dashboard Cite

Despite holding great therapeutic potential, existing protocols for in vitro chondrogenesis and hyaline cartilage production from human induced pluripotent stem cells (hiPSC) are laborious and complex with unclear long-term consequences. Here, we developed a simple xeno- and feeder-free protocol for human hyaline cartilage production in vitro using hydrogel-cultured multi-tissue organoids (MTOs). We investigate gene regulatory networks during spontaneous hiPSC-MTO differentiation using RNA sequencing and bioinformatic analyses. We find the interplays between BMPs and neural FGF pathways are associated with the phenotype transition of MTOs. We recognize TGF-beta/BMP and Wnt signaling likely contribute to the long-term maintenance of MTO cartilage growth and further adoption of articular cartilage development. By comparing the MTO transcriptome with human lower limb chondrocytes, we observe that the expression of chondrocyte-specific genes in MTO shows a strong correlation with fetal lower limb chondrocytes. Collectively, our findings describe the self-organized emergence of hyaline cartilage in MTO, its associated molecular pathways, and its spontaneous adoption of articular cartilage development trajectory.

show abstract

“…Thus, 3D stem cell derived methodologies provide access to a limitless supply of humanderived tissue which can be used to dissect complex diseases defined by "daunting polygenicity" [10] under controlled laboratory conditions [11]. Cerebral organoids mimic trimester 1 of early brain development and putatively recapitulate the epigenetic [12], transcriptomic [13,14], and proteomic [1,11] architecture that is expected of the developing mammalian brain. This also includes the recapitulation of cortical cell-type diversity and cellular events such as migration [15] and evolutionary mechanisms that support neocortical neurogenesis [16].…”

Section: Introductionmentioning

confidence: 99%

The Proteomic Architecture of Schizophrenia Cerebral Organoids Reveals Alterations in GWAS and Neuronal Development Factors

Notaras

Lodhi

Fang

et al. 2021

Preprint

View full text Add to dashboard Cite

Schizophrenia (Scz) is a brain disorder that has a typical onset in early adulthood but otherwise maintains unknown disease origins. Unfortunately, little progress has been made in understanding the molecular mechanisms underlying neurodevelopment of Scz due to ethical and technical limitations in accessing developing human brain tissue. To overcome this challenge, we have previously utilized patient-derived Induced Pluripotent Stem Cells (iPSCs) to generate self-developing, self-maturating, and self-organizing 3D brain-like tissue known as cerebral organoids. As a continuation of this prior work [1], here we provide a molecular architectural map of the developing Scz organoid proteome. Utilizing iPSCs from n = 25 human donors (n = 8 healthy Ctrl donors, and n = 17 Scz patients), we generated 3D human cerebral organoids, employed 16-plex isobaric sample-barcoding chemistry, and simultaneously subjected samples to comprehensive high-throughput liquid-chromatography/mass-spectrometry (LC/MS) quantitative proteomics. Of 3,705 proteins identified by high-throughput proteomic profiling, we identified that just ~2.62% of the organoid global proteomic landscape was differentially regulated in Scz organoids. In sum, just 43 proteins were up-regulated and 54 were down-regulated in Scz patient-derived organoids. Notably, a range of neuronal factors were depleted in Scz organoids (e.g., MAP2, TUBB3, SV2A, GAP43, CRABP1, NCAM1 etc.). Based on global enrichment analysis, alterations in key pathways that regulate nervous system development (e.g., axonogenesis, axon development, axon guidance, morphogenesis pathways regulating neuronal differentiation, as well as substantia nigra development) were perturbed in Scz patient-derived organoids. We also identified prominent alterations in two novel GWAS factors, Pleiotrophin (PTN) and Podocalyxin (PODXL), in Scz organoids. In sum, this work serves as both a report and a resource whereby researchers can leverage human-derived neurodevelopmental data from Scz patients, which can be used to mine, compare, contrast, or orthogonally validate novel factors and pathways related to Scz risk identified in datasets from observational clinical studies and other model systems.

show abstract

PsychENCODE and beyond: transcriptomics and epigenomics of brain development and organoids

Cited by 19 publications

References 179 publications

The proteomic architecture of schizophrenia iPSC-derived cerebral organoids reveals alterations in GWAS and neuronal development factors

The proteomic architecture of schizophrenia iPSC-derived cerebral organoids reveals alterations in GWAS and neuronal development factors

Self-organized emergence of hyaline cartilage in hiPSC-derived multi-tissue organoids

The Proteomic Architecture of Schizophrenia Cerebral Organoids Reveals Alterations in GWAS and Neuronal Development Factors

Contact Info

Product

Resources

About