Comprehensive multi-omics integration identifies differentially active enhancers during human brain development with clinical relevance

Yousefi, Soheil; Deng, Ruizhi; Lanko, Kristina; Salsench, Eva Medico; Nikoncuk, Anita; Linde, Herma C. van der; Perenthaler, Elena; Ham, Tjakko J. van; Mulugeta, Eskeatnaf; Barakat, Tahsin Stefan

doi:10.1186/s13073-021-00980-1

Cited by 17 publications

(21 citation statements)

References 152 publications

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“…In this study, we investigated the brain lipidome from a developmental perspective, starting at the early embryonic stage. This resource compliments previous lipidomic investigations of brain regions, cell types and membrane fractions obtained from postnatal pups and adolescent animals (Breckenridge et al, 1972;Dawson, 2015;Lauwers et al, 2016;Tulodziecka et al, 2016;Fitzner et al, 2020), and adds to the emerging multi-omics picture of neural development (Yousefi et al, 2021). Our time series analysis allowed us to identify brain lipid biomarkers that increase in abundance throughout development, starting in utero (22:6glycerophsopholipids and 18:0-sphingolipids) while cholesterol increases postnatally (Fig.…”

Section: Discussionsupporting

confidence: 54%

Lipotype acquisition during neural developmentin vivois not recapitulated in stem cell-derived neurons

Gopalan

Uden

Sprenger

et al. 2022

Preprint

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During development, different tissues acquire distinct lipotypes that are coupled to tissue function and homeostasis. In the brain, where complex membrane trafficking systems are required for neural function, specific glycerophospholipids, sphingolipids, and cholesterol are highly abundant, and defective lipid metabolism is associated with abnormal neural development and neurodegenerative disease. Notably, the production of tissue-specific lipotypes requires appropriate programming of the underlying lipid metabolic machinery, but when and how this occurs is unclear. To address this, we used high-resolution mass spectrometry-based (MSALL) lipidomics to perform a quantitative and comprehensive analysis of mouse brain development covering early embryonic and postnatal stages. We discovered a distinct bifurcation in the establishment of the neural lipotype, whereby the canonical brain lipid biomarkers 22:6-glycerophospholipids and 18:0-sphingolipids begin to be produced in utero, whereas cholesterol attains its characteristic high levels after birth. In contrast, when profiling rodent and human stem cell-derived neurons, we observed that these do not acquire a brain lipotype per se. However, upon probing the lipid metabolic wiring by supplementing brain lipid precursors, we found that the stem cell-derived neurons were partially able to establish a brain-like lipotype, demonstrating that the cells are partially metabolically committed. Altogether, our report provides an extensive lipidomic resource for brain development and highlights a potential challenge in using stem cell-derived neurons for mechanistic studies of lipid biochemistry, membrane biology and biophysics that can be mitigated by further optimizing in vitro differentiation protocols.

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Section: Discussionsupporting

confidence: 54%

Lipotype acquisition during neural developmentin vivois not recapitulated in stem cell-derived neurons

Gopalan

Uden

Sprenger

et al. 2022

Preprint

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“…Originating from asymmetric divisions of neural progenitors in the ventricular zone (VZ), neurons undergo earlier neuronal development programs, including migration and projection development, followed by later maturation processes, including synaptic development and pruning, to gain their locational and functional identities in different layers of the cortex (Campbell 2005; Götz and Huttner 2005; Luo and O’Leary 2005). These steps are finely tuned by a sophisticated network of cis-regulatory elements (e.g., promoters and enhancers), trans-regulatory factors (e.g., transcriptional factors(TFs) and histone modifying complexes), as well as epigenetic regulation (e.g., changes in chromatin accessibility and histone modifications) (Dixit et al 2014; Lomvardas and Maniatis 2016; Nitarska et al 2016; Olson et al 2001; Trevino et al 2020; Yousefi et al 2021). Thus, proper activation and repression of those early neuronal development programs in a timely manner is crucial for both generation of neurons and their later maturation and fate specification (Yuan et al 2022).…”

Section: Introductionmentioning

confidence: 99%

MYT1L is required for suppressing earlier neuronal development programs in the adult mouse brain

Chen¹,

Fuhler

Noguchi

et al. 2022

Preprint

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In vitro studies indicate the neurodevelopmental disorder gene Myelin Transcription Factor 1 Like (MYT1L) suppresses non-neuronal lineage genes during fibroblast-to-neuron direct differentiation. However, MYT1L's molecular and cellular functions during differentiation in the mammalian brain have not been fully characterized. Here, we found that MYT1L loss leads to up-regulated deep layer (DL) but down-regulated upper layer (UL) neuron gene expression, corresponding to an increased ratio of DL/UL neurons in mouse cortex. To define potential mechanisms, we conducted Cleavage Under Targets & Release Using Nuclease (CUT&RUN) to map MYT1L binding targets in mouse developing cortex and adult prefrontal cortex (PFC), and to map epigenetic changes due to MYT1L mutation. We found MYT1L mainly binds to open chromatin, but with different transcription factor co-occupancies between promoters and enhancers. Likewise, multi-omic dataset integration revealed that, at promoters, MYT1L loss does not change chromatin accessibility but does increase H3K4me3 and H3K27ac, activating both a subset of earlier neuronal development genes as well as Bcl11b, a key regulator for DL neuron development. Meanwhile, we discovered that MYT1L normally represses the activity of neurogenic enhancers associated with neuronal migration and neuronal projection development by closing chromatin structures and promoting removal of active histone marks. Further, we show MYT1L interacts with SIN3B and HDAC2 in vivo, providing potential mechanisms underlying any repressive effects on histone acetylation and gene expression. Overall, our findings provide a comprehensive map of MYT1L binding in vivo and mechanistic insights to how MYT1L facilitates neuronal maturation.

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“…The pattern of variant proportion on different genomic regions for candidate trans-eQTLs is similar to that for cis-eQTLs but not cQTLs. We also calculated the enrichment of the QTLs in previously published brain enhancer lists [ 31 ] and found the enrichment patterns to be similar across these enhancers (Additional file 6 : Fig. S6A).…”

Section: Resultsmentioning

confidence: 96%

Illuminating links between cis-regulators and trans-acting variants in the human prefrontal cortex

et al. 2022

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Background Neuropsychiatric disorders afflict a large portion of the global population and constitute a significant source of disability worldwide. Although Genome-wide Association Studies (GWAS) have identified many disorder-associated variants, the underlying regulatory mechanisms linking them to disorders remain elusive, especially those involving distant genomic elements. Expression quantitative trait loci (eQTLs) constitute a powerful means of providing this missing link. However, most eQTL studies in human brains have focused exclusively on cis-eQTLs, which link variants to nearby genes (i.e., those within 1 Mb of a variant). A complete understanding of disease etiology requires a clearer understanding of trans-regulatory mechanisms, which, in turn, entails a detailed analysis of the relationships between variants and expression changes in distant genes. Methods By leveraging large datasets from the PsychENCODE consortium, we conducted a genome-wide survey of trans-eQTLs in the human dorsolateral prefrontal cortex. We also performed colocalization and mediation analyses to identify mediators in trans-regulation and use trans-eQTLs to link GWAS loci to schizophrenia risk genes. Results We identified ~80,000 candidate trans-eQTLs (at FDR<0.25) that influence the expression of ~10K target genes (i.e., “trans-eGenes”). We found that many variants associated with these candidate trans-eQTLs overlap with known cis-eQTLs. Moreover, for >60% of these variants (by colocalization), the cis-eQTL’s target gene acts as a mediator for the trans-eQTL SNP's effect on the trans-eGene, highlighting examples of cis-mediation as essential for trans-regulation. Furthermore, many of these colocalized variants fall into a discernable pattern wherein cis-eQTL’s target is a transcription factor or RNA-binding protein, which, in turn, targets the gene associated with the candidate trans-eQTL. Finally, we show that trans-regulatory mechanisms provide valuable insights into psychiatric disorders: beyond what had been possible using only cis-eQTLs, we link an additional 23 GWAS loci and 90 risk genes (using colocalization between candidate trans-eQTLs and schizophrenia GWAS loci). Conclusions We demonstrate that the transcriptional architecture of the human brain is orchestrated by both cis- and trans-regulatory variants and found that trans-eQTLs provide insights into brain-disease biology.

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Comprehensive multi-omics integration identifies differentially active enhancers during human brain development with clinical relevance

Cited by 17 publications

References 152 publications

Lipotype acquisition during neural developmentin vivois not recapitulated in stem cell-derived neurons

Lipotype acquisition during neural developmentin vivois not recapitulated in stem cell-derived neurons

MYT1L is required for suppressing earlier neuronal development programs in the adult mouse brain

Illuminating links between cis-regulators and trans-acting variants in the human prefrontal cortex

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