(A) The causal chain of Mendelian Disorder of the Epigenetic Machinery (MDEM) pathogenesis: the genetic disruption of an epigenetic regulator leads to epigenetic and transcriptomic alterations, …
See Materials and methods for details. Panel (A) corresponds to two experiments, and panel (B) corresponds to three experiments. The distributions were derived after 1000 simulations.
(A) The distribution of p-values from the KS2 vs. wild-type differential accessibility analysis for promoter peaks, stratified according to whether the same promoter peaks are significantly …
Coordinates of shared differentially accessible promoter peaks in Kabuki type 1 (KS1) and Kabuki type 2 (KS2) syndromes, along with the corresponding logFC changes.
Coordinates of shared differentially accessible promoter peaks in Kabuki type 1 (KS1), Kabuki type 2 (KS2), and Rubinstein-Taybi type 1 (RT1) syndromes, along with the corresponding logFC changes.
Coordinates of shared differentially accessible distal regulatory element peaks in Kabuki type 1 (KS1) and Kabuki type 2 (KS2) syndromes, along with the corresponding logFC changes.
Coordinates of shared differentially accessible distal regulatory element peaks in Kabuki type 1 (KS1), Kabuki type 2 (KS2), and Rubinstein-Taybi type 1 (RT1) syndromes, along with the corresponding logFC changes.
Estimated surrogate variables for the differential accessibility and differential expression analyses.
Each point corresponds to a mouse. The black points correspond to wild-type mice from the Kabuki cohorts, and the gray points correspond to wild-type mice from the Rubinstein-Taybi cohort.
(A) The distribution of p-values from the KS2 vs. wild-type differential accessibility analysis for peaks at distal regulatory elements (defined as peaks not within ±2 kb from the TSS), stratified …
(A) The proportion of promoters with differentially expressed downstream genes in Kabuki type 1 (KS1), Kabuki type 2 (KS2), and Rubinstein-Taybi type 1 (RT1) syndromes, estimated for the top ranked …
Differentially expressed genes downstream of differentially accessible promoter peaks, along with the corresponding p-values and logFC changes.
The horizontal lines correspond to the estimated proportion of non-differential genes (see Materials and methods). For Kabuki type 1 (KS1) syndrome, both the proportion estimated with the bootstrap …
(A) The distribution of p-values from the KS2 vs. wild-type differential expression analysis, stratified according to whether the same genes are significantly differentially expressed in KS1 (FDR < …
Shared differentially expressed genes in Kabuki type 1 (KS1) and Kabuki types 2 (KS2) syndromes, along with the corresponding logFC changes.
Shared differentially expressed genes in Kabuki type 1 (KS1), Kabuki type 2 (KS2), and Rubinstein-Taybi type 1 (RT1), along with the corresponding logFC changes.
Transcription factor motifs enriched in peaks found in promoters of differentially expressed genes.
Each point corresponds to a mouse. The black points correspond to wild-type mice from the Kabuki cohorts, and the gray points correspond to wild-type mice from the Rubinstein-Taybi cohort.
(A) The Wilcoxon rank-sum test statistic (red vertical line) computed after assembling a list of genes encoding TFs expressed in B cells (Materials and methods), and comparing the distribution of …
Top 20 Reactome enriched pathways, using shared differentially expressed genes in Kabuki type 1 (KS1), Kabuki type 2 (KS2), and Rubinstein-Taybi type 1 (RT1) syndromes.
Top 20 Reactome enriched pathways, using genes with shared differentially accessible promoters in Kabuki type 1 (KS1), Kabuki type 2 (KS2), and Rubinstein-Taybi type 1 (RT1) syndromes.
Serum IgA levels measured in the two types of Kabuki syndrome and wild-type littermates.
Gene name | Gene expression | Promoter accessibility | Gene function |
---|---|---|---|
Pard3b | Up | Up | Cell division and cell polarization processes |
Pbx1 | Up | Up | Transcription factor |
Epm2a | Up | Up | Serine/threonine/tyrosine phosphatase |
Zfp365 | Up | Up | Transcription factor |
Ccdc88a | Up | Up | Actin binding protein |
Tanc2 | Up | Up | Synaptic scaffolding protein |
Dip2c | Up | Up | Protein interacting with transcription factors |
Kif13a | Up | Up | Microtubule-based motor protein |
Spry2 | Up | Up | Inhibitory activity on receptor tyrosine kinase signaling proteins |
Ndrg1 | Up | Up | N-myc downregulated gene family member |
Ebi3 | Down | Down | Interleukin subunit |
Ppdpf | Down | Down | Regulator of exocrine pancreas development |
Golim4 | Up | Up | Golgi protein |
Reln | Up | Up | Secreted extracellular matrix protein |
Amz1 | Down | Down | Zinc metalloproteinase |
Slc29a4 | Up | Up | Monoamine transporter |
Bicd1 | Up | Up | Role in intracellular cargo transport |
Slc25a4 | Up | Up | Member of the mitochondrial carrier subfamily |
Nr3c2 | Up | Up | Mineralocorticoid receptor |
Zfp827 | Up | Up | Transcription factor |
Slc36a4 | Up | Up | Amino acid transporter |
Arhgef12 | Up | Up | Guanine exchange factor |
Tbc1d2b | Up | Up | GTP-ase activating protein |
Cask | Up | Up | Calcium-calmodulin-dependent serine protein kinase |
Dmd | Up | Up | Connects cytoskeleton and the extracellular matrix |
Maged1 | Up | Up | p75 neurotrophin receptor mediated program |
Chic1 | Up | Up | Cysteine-rich hydrophobic (CHIC) domain containing protein |
Gprasp1 | Up | Up | G protein-coupled receptor interacting protein |
Col4a5 | Up | Up | Major collagen of basement membrane |
Reagent type (species) or resource | Designation | Source or reference | Identifiers | Additional information |
Strain, strain background (Mus musculus, both sexes) | Kmt2d+/βGeo mice (fully backcrossed to C57BL/6J) | Originally from Bay Genomics and described in PMID:2527309625273096. | Kmt2d+/βGeo,Mll2Gt(RRt024)BygRRID:MGI:5829565 | A previously characterized mouse model of Kabuki syndrome (type 1). |
Strain, strain background (Mus musculus, females only) | Kdm6a± mice (fully backcrossed to C57BL/6J, observed male lethality) | Ordered from EMMA (European Mouse Mutant Archive) | Kdm6a+/, Kdm6atm1d(EUCOMM)WtsiMGI:4434460 | A previously characterized mouse model of Kabuki syndrome (type 2). Transition from Kdm6atm1a(EUCOMM)Wtsi to Kdm6atm1d(EUCOMM)Wtsi performed in Bjornsson laboratory. |
Strain, strain background (Mus musculus, both sexes) | Crebbp±mice (fully backcrossed to C57BL/6J) | Ordered from Jackson laboratory and described in PMID:10673499 | Crebbp+/-Crebbptm1Dli, RRID:MGI:2175793 | A previously characterized mouse model of Rubinstein-Taybi syndrome (type 1). |
Sequence-based reagent | βGeo F | This paper | PCR primers | CAAATGGCGATTACCGTTGA |
Sequence-based reagent | βGeo R | This paper | PCR primers | TGCCCAGTCATAGCCGAATA |
Sequence-based reagent | Tcrd (control) F | This paper | PCR primers | CAAATGTTGCTTGTCTGGTG |
Sequence-based reagent | Tcrd (control) R | This paper | PCR primers | GTCAGTCGAGTGCACAGTTT |
Sequence-based reagent | Kdm6aTm1c F | This paper | PCR primers | AAGGCGCATAACGATACCAC |
Sequence-based reagent | Kdm6aTm1c, Floxed LR | This paper | PCR primers | ACTGATGGCGAGCTCAGACC |
Sequence-based reagent | Tcrd (control) F- | This paper | PCR primers | CAAATGTTGCTTGTCTGGTG |
Sequence-based reagent | Tcrd (control) R | This paper | PCR primers | GTCAGTCGAGTGCACAGTTT |
Sequence-based reagent | CrebbpR-T F | This paper | PCR primers | TAAGCAGCAGCATCCTTTGG |
Sequence-based reagent | CrebbpR-T_WT | This paper | PCR primers | CCTGACAATGTGTCATGTGAT |
Sequence-based reagent | CrebbpR_T_MUT R: | This paper | PCR primers | ATGCTCCAGACTGCCTTGGGA |
Commercial assay or kit | IgA ELISA kit | Thermo | Catalog # EMIGA | |
Commercial assay or kit | CD19 positive selection | Miltenyi | 130-052-201 | |
Commercial assay or kit | Tagmentation | IlluminaNextera | FC-121–1030 | |
Commercial assay or kit | Digitonin | Promega | G9441 | |
Commercial assay or kit | DNA clean and concentration kit | Zymo | D4013 | |
Commercial assay or kit | Select A size purification | Zymo | D4080 | |
Commercial assay or kit | DNA high sensitivity | Agilent | 5067–4626 | |
Commercial assay or kit | Qubit dsDNA HS | Thermo | Q32851 | |
Commercial assay or kit | Direct-zol RNA microprep | Zymo | R2060 | |
Commercial assay or kit | Quant-iT RiboGreen | Thermo | R11490 | |
Commercial assay or kit | RNA HS Assay kit | Thermo | Q32852 | |
Commercial assay or kit | RNA 6000 Pico | Agilent | 5067–1513 | |
Commercial assay or kit | NEBNext Poly(A) mRNA isolation module | New England Biolabs | E7490 | |
Commercial assay or kit | NEBNext Ultra II Directional RNA Library Prep kit | New England Biolabs | E7760/E7765 | |
Commercial assay or kit | KAPA library Quantification kit | KAPA | KK4824 | |
Software, algorithm | BowTie2 | PMID:22388286 | RRID:SCR_016368 | Default parameters |
Software, algorithm | Samtools | PMID:19505943 | RRID:SCR_002105 | |
Software, algorithm | MACS2 | PMID:18798982 | RRID:SCR_013291 | Keep-dup = all |
Software, algorithm | DESeq2 | PMID:25516281 | RRID:SCR_015687 | |
Software, algorithm | Surrogate Variable Analysis | PMID:17907809 | RRID:SCR_012836 | |
Software, algorithm | Salmon | PMID:28263959 | V0.10RRID:SCR_017036 | |
Other | GEO submission of all data | Accession GSE162181 | RRID:SCR_005012 |