Diabetic Kidney Disease

Multimodal single cell sequencing implicates chromatin accessibility and genetic background in diabetic kidney disease progression

cellxgene_census

Info

cellxgene_census/dkd
Wilson et al. (2022)
1.28 GiB
02-02-2024
39176 cells × 27980 genes

Used in

No related benchmarks found.

Description

Multimodal single cell sequencing is a powerful tool for interrogating cell-specific changes in transcription and chromatin accessibility. We performed single nucleus RNA (snRNA-seq) and assay for transposase accessible chromatin sequencing (snATAC-seq) on human kidney cortex from donors with and without diabetic kidney disease (DKD) to identify altered signaling pathways and transcription factors associated with DKD. Both snRNA-seq and snATAC-seq had an increased proportion of VCAM1+ injured proximal tubule cells (PT_VCAM1) in DKD samples. PT_VCAM1 has a pro-inflammatory expression signature and transcription factor motif enrichment implicated NFkB signaling. We used stratified linkage disequilibrium score regression to partition heritability of kidney-function-related traits using publicly-available GWAS summary statistics. Cell-specific PT_VCAM1 peaks were enriched for heritability of chronic kidney disease (CKD), suggesting that genetic background may regulate chromatin accessibility and DKD progression. snATAC-seq found cell-specific differentially accessible regions (DAR) throughout the nephron that change accessibility in DKD and these regions were enriched for glucocorticoid receptor (GR) motifs. Changes in chromatin accessibility were associated with decreased expression of insulin receptor, increased gluconeogenesis, and decreased expression of the GR cytosolic chaperone, FKBP5, in the diabetic proximal tubule. Cleavage under targets and release using nuclease (CUT&RUN) profiling of GR binding in bulk kidney cortex and an in vitro model of the proximal tubule (RPTEC) showed that DAR co-localize with GR binding sites. CRISPRi silencing of GR response elements (GRE) in the FKBP5 gene body reduced FKBP5 expression in RPTEC, suggesting that reduced FKBP5 chromatin accessibility in DKD may alter cellular response to GR. We developed an open-source tool for single cell allele specific analysis (SALSA) to model the effect of genetic background on gene expression. Heterozygous germline single nucleotide variants (SNV) in proximal tubule ATAC peaks were associated with allele-specific chromatin accessibility and differential expression of target genes within cis-coaccessibility networks. Partitioned heritability of proximal tubule ATAC peaks with a predicted allele-specific effect was enriched for eGFR, suggesting that genetic background may modify DKD progression in a cell-specific manner.

Preview

dataset is an AnnData object with n_obs × n_vars = 39176 × 27980 with slots:

Reference

Name Description Type Data type Size
obs
assay Type of assay used to generate the cell data, indicating the methodology or technique employed. vector category 39176
assay_ontology_term_id Experimental Factor Ontology (EFO:) term identifier for the assay, providing a standardized reference to the assay type. vector category 39176
batch A batch identifier. This label is very context-dependent and may be a combination of the tissue, assay, donor, etc. vector category 39176
cell_type Classification of the cell type based on its characteristics and function within the tissue or organism. vector category 39176
cell_type_ontology_term_id Cell Ontology (CL:) term identifier for the cell type, offering a standardized reference to the specific cell classification. vector category 39176
dataset_id Identifier for the dataset from which the cell data is derived, useful for tracking and referencing purposes. vector category 39176
development_stage Stage of development of the organism or tissue from which the cell is derived, indicating its maturity or developmental phase. vector category 39176
development_stage_ontology_term_id Ontology term identifier for the developmental stage, providing a standardized reference to the organism’s developmental phase. If the organism is human (organism_ontology_term_id == 'NCBITaxon:9606'), then the Human Developmental Stages (HsapDv:) ontology is used. If the organism is mouse (organism_ontology_term_id == 'NCBITaxon:10090'), then the Mouse Developmental Stages (MmusDv:) ontology is used. Otherwise, the Uberon (UBERON:) ontology is used. vector category 39176
disease Information on any disease or pathological condition associated with the cell or donor. vector category 39176
disease_ontology_term_id Ontology term identifier for the disease, enabling standardized disease classification and referencing. Must be a term from the Mondo Disease Ontology (MONDO:) ontology term, or PATO:0000461 from the Phenotype And Trait Ontology (PATO:). vector category 39176
donor_id Identifier for the donor from whom the cell sample is obtained. vector category 39176
is_primary_data Indicates whether the data is primary (directly obtained from experiments) or has been computationally derived from other primary data. vector bool 39176
self_reported_ethnicity Ethnicity of the donor as self-reported, relevant for studies considering genetic diversity and population-specific traits. vector category 39176
self_reported_ethnicity_ontology_term_id Ontology term identifier for the self-reported ethnicity, providing a standardized reference for ethnic classifications. If the organism is human (organism_ontology_term_id == 'NCBITaxon:9606'), then the Human Ancestry Ontology (HANCESTRO:) is used. vector category 39176
sex Biological sex of the donor or source organism, crucial for studies involving sex-specific traits or conditions. vector category 39176
sex_ontology_term_id Ontology term identifier for the biological sex, ensuring standardized classification of sex. Only PATO:0000383, PATO:0000384 and PATO:0001340 are allowed. vector category 39176
size_factors The size factors created by the normalisation method, if any. vector float32 39176
soma_joinid If the dataset was retrieved from CELLxGENE census, this is a unique identifier for the cell. vector int64 39176
suspension_type Type of suspension or medium in which the cells were stored or processed, important for understanding cell handling and conditions. vector category 39176
tissue Specific tissue from which the cells were derived, key for context and specificity in cell studies. vector category 39176
tissue_general General category or classification of the tissue, useful for broader grouping and comparison of cell data. vector category 39176
tissue_general_ontology_term_id Ontology term identifier for the general tissue category, aiding in standardizing and grouping tissue types. For organoid or tissue samples, the Uber-anatomy ontology (UBERON:) is used. The term ids must be a child term of UBERON:0001062 (anatomical entity). For cell cultures, the Cell Ontology (CL:) is used. The term ids cannot be CL:0000255, CL:0000257 or CL:0000548. vector category 39176
tissue_ontology_term_id Ontology term identifier for the tissue, providing a standardized reference for the tissue type. For organoid or tissue samples, the Uber-anatomy ontology (UBERON:) is used. The term ids must be a child term of UBERON:0001062 (anatomical entity). For cell cultures, the Cell Ontology (CL:) is used. The term ids cannot be CL:0000255, CL:0000257 or CL:0000548. vector category 39176
var
feature_id Unique identifier for the feature, usually a ENSEMBL gene id. vector object 27980
feature_name A human-readable name for the feature, usually a gene symbol. vector object 27980
hvg Whether or not the feature is considered to be a ‘highly variable gene’ vector bool 27980
hvg_score A ranking of the features by hvg. vector float64 27980
soma_joinid If the dataset was retrieved from CELLxGENE census, this is a unique identifier for the feature. vector int64 27980
obsp
knn_connectivities K nearest neighbors connectivities matrix. sparsematrix float32 39176 × 39176
knn_distances K nearest neighbors distance matrix. sparsematrix float64 39176 × 39176
obsm
X_pca The resulting PCA embedding. densematrix float32 39176 × 50
varm
pca_loadings The PCA loadings matrix. densematrix float32 27980 × 50
layers
counts Raw counts sparsematrix float32 39176 × 27980
normalized Normalised expression values sparsematrix float32 39176 × 27980
uns
dataset_description Long description of the dataset. atomic str 1
dataset_id A unique identifier for the dataset. This is different from the obs.dataset_id field, which is the identifier for the dataset from which the cell data is derived. atomic str 1
dataset_name A human-readable name for the dataset. atomic str 1
dataset_organism The organism of the sample in the dataset. atomic str 1
dataset_reference Bibtex reference of the paper in which the dataset was published. atomic str 1
dataset_summary Short description of the dataset. atomic str 1
dataset_url Link to the original source of the dataset. atomic str 1
knn Supplementary K nearest neighbors data. dict 3
normalization_id Which normalization was used atomic str 1
pca_variance The PCA variance objects. dict 2

References

Wilson, Parker C., Yoshiharu Muto, Haojia Wu, Anil Karihaloo, Sushrut S. Waikar, and Benjamin D. Humphreys. 2022. “Multimodal Single Cell Sequencing Implicates Chromatin Accessibility and Genetic Background in Diabetic Kidney Disease Progression.” Nature Communications 13 (1). https://doi.org/10.1038/s41467-022-32972-z.