Gene expression across mammalian organ development

Cardoso-Moreira, Margarida; Halbert, Jean; Valloton, Delphine; Velten, Britta; Chen, Chunyan; Shao, Yi; Liechti, Angélica; Ascenção, Kelly; Rummel, Coralie; Ovchinnikova, Svetlana; Mazin, Pavel; Xénarios, Ioannis; Harshman, Keith; Mort, Matthew; Cooper, David Neil; Sandi, Carmen; Soares, Michael J.; Ferreira, Paula; Afonso, Sandra; Carneiro, Miguel; Turner, James M. A.; VandeBerg, John L.; Fallahshahroudi, Amir; Jensen, Per; Behr, Ruediger; Lisgo, Steven; Lindsay, Susan; Khaitovich, Philipp; Huber, Wolfgang; Baker, Julie C.; Anders, Simon; Zhang, Yong E.; Kaessmann, Henrik

doi:10.1038/s41586-019-1338-5

Cited by 506 publications

(646 citation statements)

References 67 publications

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“…This observation is in keeping with previous studies that have shown most lncRNAs are tissue-specific with the highest proportion being specific to brain 43 . Similarly, the enrichment for nervous system-related pathways within CNCRs, which is representative of recent purifying selection, is in keeping with the lowest proportion of positively-selected genes being present in brain tissues from previous studies of mammalian organ development 44 . We also find enrichment of spinal cord-associated genes that may relate to the uniquely human monosynaptic corticomotoneuronal pathways implicated in humanspecific dexterity and digital motor control 45,46 , the disruption of which may lead to amyotrophic lateral sclerosis 47 .…”

Section: Discussionsupporting

confidence: 69%

Human-lineage-specific genomic elements: relevance to neurodegenerative disease and APOE transcript usage

Chen

Zhang

Reynolds

et al. 2020

Preprint

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Knowledge of genomic features specific to the human lineage may provide insights into brain-related diseases. We leverage high-depth whole genome sequencing data to generate a combined annotation identifying regions simultaneously depleted for genetic variation (constrained regions) and poorly conserved across primates. We propose that these constrained, non-conserved regions (CNCRs) have been subject to human-specific purifying selection and are enriched for brain-specific elements. We find that CNCRs are depleted from protein-coding genes but enriched within lncRNAs. We demonstrate that per-SNP heritability of a range of brain-relevant phenotypes are enriched within CNCRs. We find that genes implicated in neurological diseases have high CNCR density, including APOE, highlighting an unannotated intron-3 retention event. Using human brain RNA-sequencing data, we show the intron-3-retaining transcript/s to be more abundant in Alzheimer's disease with more severe tau and amyloid pathological burden. Thus, we demonstrate the importance of human-lineage-specific sequences in brain development and neurological disease. We release our annotation through vizER

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Section: Discussionsupporting

confidence: 69%

Human-lineage-specific genomic elements: relevance to neurodegenerative disease and APOE transcript usage

Chen

Zhang

Reynolds

et al. 2020

Preprint

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“…S5A ) . The expression of METTL7B was also enriched in the human and macaque cerebrum as compared to the cerebrum of mouse, rat, rabbit, and opossum (Cardoso-Moreira et al, 2019) (Fig. S5B ) .…”

Section: Resultsmentioning

confidence: 98%

“…B , RNA-seq expression of METTL7B in the brain (forebrain/cerebrum) of multiple species at different developmental stages. Expression data was obtained from Cardoso-Moreira et al 2019. C , RNA-seq expression of METTL7B in human NCX.…”

Section: Figure S1 (Related To Figure 1)mentioning

confidence: 99%

Molecular Diversity Among Adult Human Hippocampal and Entorhinal Cells

Franjic

Choi

Škarica

et al. 2020

Preprint

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RESULTS 104Transcriptomic diversity of hippocampal and entorhinal cells 105 To survey the transcriptomic diversity and functional specification of the mesial temporal 106 cortex, we used snRNA-seq to profile five subregions of the hippocampal-entorhinal system 107 6 collected from fresh frozen postmortem brains of clinically unremarkable human donors. These 108 specimens were selected from a larger pool of postmortem human brains based on the quality 109 of isolated nuclei and RNA. Taking into consideration dramatic cytoarchitectonic variations, 110 we microdissected the hippocampal formation (DG, CA2-4, CA1, and subiculum) and EC for 111 a total of five subregions (Fig. 1A). 112 Unbiased isolation of nuclei using our previously described protocol (Li et al., 2018; 113 Zhu et al., 2018) followed by snRNA barcoding, cDNA sequencing and quality filtering yielded 114 108,315 high-quality single-nucleus profiles from all five subregions ( Fig. 1A, S1A-D). 115 Analysis of the expression of genes known to be enriched in major cell subpopulations 116 suggested these included 44,697 neurons, of which 35,768 (80.02%) were glutamatergic 117 excitatory neurons (expressing the gene encoding the vesicular glutamate transporter SLC17A7) 118 and 8,929 (19.98%) were GABAergic inhibitory neurons (expressing the gene encoding the 119 GABA synthesis enzyme GAD1), reflecting the expected 80:20 ratio of these populations. In 120 addition, we identified 63,618 (58.73% of the total population) non-neuronal cells. 121 We next analyzed the transcriptomes of those nuclei on the Uniform Manifold 122 Approximation and Projection (UMAP) layout representing their similarities at cellular 123 granularity ( Fig. 1B-D). Iterative clustering defined 69 transcriptomically distinct cell clusters 124 representing presumptive cell types across all individuals (donors). These transcriptomically 125 diverse subpopulations were organized into a dendrogramatic taxonomy reflecting their gene 126 expression patterns and were subsequently assigned identities commensurate with predicted cell 127 types. This allowed us to identify 26 subtypes of excitatory neurons (Fig. 1E and S2A-B), 23 128 inhibitory neuron subtypes ( Fig. 1E and S2C-D), and 20 non-neuronal cell types and subtypes 129 ( Fig. 1E and S2E-F). Similar single nucleus approaches applied to human neocortical samples 130 7 yielded comparable numbers and distributions of cell populations in medial temporal gyrus 131 (MTG) (Hodge et al., 2019)and dorso-lateral prefrontal cortex (dlPFC) (Li et al., 2018)(Fig. 132 S1E-F). 133Within excitatory neuron subtypes, we found marked transcriptional diversity that 134 reflects differences in the cytoarchitectonic organization among the subregions of the HIP (DG, 135 CA2-4, CA1, and subiculum) and EC (Fig. 1E). For example, in addition to ADCYAP1-136 expressing mossy cells in DG, we found three distinct subclusters of PROX1-expressing granule 137 cells. We also identified excitatory neurons in CA1 and CA2-4 that could be deconstructe...

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“…We analyzed a rat RNA-seq transcriptomic BodyMap across 11 organs (15) and revealed that Coq10a is predominantly expressed in the skeletal muscle and heart at 21 weeks of age ( Figure 1A) while its paralog Coq10b is highly expressed in the adrenal gland but present in most other organs at a low level ( Figure S1A). In addition, a recent detailed analysis of gene expression across mouse organ development showed that cardiac expression of Coq10a begins around E15.5, rapidly increases postnatally and keeps increasing by postnatal day 63 (P63) ( Figure 1B); Coq10b expression follows a similar temporal pattern in the heart ( Figure S1B) (16). In the adult mouse heart, Coq10a expression is 4-5 folds higher than Coq10b (Figure 1B and S1B).…”

Section: Coq10a Is a Novel Mitochondrial Protein Predominantly Expresmentioning

confidence: 89%

Loss of a novel striated muscle-enriched mitochondrial protein Coq10a enhances postnatal cardiac hypertrophic growth

Hirose

Chang

et al. 2019

Preprint

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Postnatal mammalian cardiomyocytes undergo a major transition from hyperplasia (increases in cell numbers) to hypertrophy (expansion in cell size). This process is accompanied by rapid mitochondrial biogenesis and metabolic switches to meet the demand of increased cardiac output.Although most mitochondrial components express ubiquitously, recent transcriptomic and proteomic analyses have discovered numerous tissue-specific mitochondrial proteins whose physiological functions are largely unknown. Here we report that a highly evolutionarily conserved mitochondrial protein Coq10a is predominantly expressed in mammalian cardiac and skeletal muscles, and is highly up-regulated around birth in a thyroid hormone-dependent manner. Deletion of Coq10a by CRISPR/Cas9 leads to enhanced cardiac growth after birth. Surprisingly, adult Coq10a mutant mice maintain the hypertrophic heart phenotype with increased levels of coenzyme Q (CoQ) per cardiomyocyte, preserved cardiac contractile function and mitochondrial respiration, which contrasts with reported mice and humans with mutations in other Coq family genes. Further RNA-seq analysis and mitochondrial characterization suggest an increase of mitochondrial biogenesis in the Coq10a

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Gene expression across mammalian organ development

Cited by 506 publications

References 67 publications

Human-lineage-specific genomic elements: relevance to neurodegenerative disease and APOE transcript usage

Human-lineage-specific genomic elements: relevance to neurodegenerative disease and APOE transcript usage

Molecular Diversity Among Adult Human Hippocampal and Entorhinal Cells

Loss of a novel striated muscle-enriched mitochondrial protein Coq10a enhances postnatal cardiac hypertrophic growth

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