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| Status |
Public on Mar 30, 2024 |
| Title |
Growth retardation in a mouse model of Kabuki syndrome 2 bears mechanistic similarities to Kabuki syndrome 1. |
| Organism |
Mus musculus |
| Experiment type |
Expression profiling by high throughput sequencing
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| Summary |
Growth deficiency is a characteristic feature of both Kabuki syndrome 1 (KS1) and Kabuki syndrome 2 (KS2), Mendelian disorders of the epigenetic machinery with similar phenotypes but distinct genetic etiologies. We previously described skeletal growth deficiency in a mouse model of KS1 and further established that a Kmt2d -/- chondrocyte model of KS1 exhibits precocious differentiation. Here we characterized growth deficiency in a mouse model of KS2, Kdm6a tm1d/+. We show that Kdm6a tm1d/+ mice have decreased femur and tibia length compared to controls and exhibit abnormalities in cortical and trabecular bone structure. Kdm6a tm1d/+ growth plates are also shorter, due to decreases in hypertrophic chondrocyte size and hypertrophic zone height. Given these disturbances in the growth plate, we generated Kdm6a -/- chondrogenic cell lines. Similar to our prior in vitro model of KS1, we found that Kdm6a -/- cells undergo premature, enhanced differentiation towards chondrocytes compared to Kdm6a +/+ controls. RNA-seq showed that Kdm6a -/- cells have a distinct transcriptomic profile that indicates dysregulation of cartilage development. Finally, we performed RNA-seq simultaneously on Kmt2d -/-, Kdm6a -/-, and control lines at Days 7 and 14 of differentiation. This revealed surprising resemblance in gene expression between Kmt2d -/- and Kdm6a -/- at both time points and indicates that the similarity in phenotype between KS1 and KS2 also exists at the transcriptional level.
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| Overall design |
We generated Kdm6a -/- and Kdm6a +/+ cell lines from the murine teratocarcinoma parental cell line ATDC5 using CRISPR-Cas9. For the first experiment, we differentiated Kdm6a -/- and Kdm6a +/+ cells towards chondrocytes for 14 days. We then harvested RNA and performed library prep for RNA-seq. For the second experiment, we performed chondrogenic differentiation on Kdm6a -/- and Kdm6a +/+ cells as well as Kmt2d -/- and Kmt2d +/+ cell lines, previously generated from the same parental ATDC5 cell line. We collected samples for RNA-seq at both Day 7 and Day 14 of differentiation for all cell lines.
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| Contributor(s) |
Gao CW, Hansen KD, Fahrner JA |
| Citation(s) |
38857303 |
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| Submission date |
Mar 26, 2024 |
| Last update date |
Jun 28, 2024 |
| Contact name |
Christine W Gao |
| E-mail(s) |
cgao13@jhmi.edu
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| Organization name |
Johns Hopkins University School of Medicine
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| Street address |
733 N. Broadway, Rm 406
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| City |
Baltimore |
| State/province |
MD |
| ZIP/Postal code |
21205 |
| Country |
USA |
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| Platforms (1) |
| GPL24247 |
Illumina NovaSeq 6000 (Mus musculus) |
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| Samples (32)
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| GSM8171469 |
Kdm6a +/+ line 2, D14, exp1 |
| GSM8171470 |
Kdm6a +/+ line 3, D14, exp1 |
| GSM8171471 |
Kdm6a +/+ line 4, D14, exp1 |
| GSM8171472 |
Kdm6a -/- line 3, D14, exp1 |
| GSM8171473 |
Kdm6a +/+ line 5, D14, exp1 |
| GSM8171474 |
Kdm6a -/- line 4, D14, exp1 |
| GSM8171475 |
Kdm6a -/- line 5, D14, exp1 |
| GSM8171476 |
Kdm6a -/- line 2, D7, exp2 |
| GSM8171477 |
Kdm6a -/- line 3, D7, exp2 |
| GSM8171478 |
Kdm6a -/- line 5, D7, exp2 |
| GSM8171479 |
Kmt2d +/+ line 1, D7, exp2 |
| GSM8171480 |
Kmt2d +/+ line 2, D7, exp2 |
| GSM8171481 |
Kmt2d +/+ line 3, D7, exp2 |
| GSM8171482 |
Kmt2d -/- line 1, D7, exp2 |
| GSM8171483 |
Kmt2d -/- line 2, D7, exp2 |
| GSM8171484 |
Kdm6a +/+ line 2, D7, exp2 |
| GSM8171485 |
Kdm6a +/+ line 3, D7, exp2 |
| GSM8171486 |
Kdm6a +/+ line 4, D7, exp2 |
| GSM8171487 |
Kdm6a -/- line 2, D14, exp2 |
| GSM8171488 |
Kdm6a -/- line 3, D14, exp2 |
| GSM8171489 |
Kdm6a -/- line 5, D14, exp2 |
| GSM8171490 |
Kmt2d +/+ line 1, D14, exp2 |
| GSM8171491 |
Kmt2d +/+ line 2, D14, exp2 |
| GSM8171492 |
Kmt2d +/+ line 3, D14, exp2 |
| GSM8171493 |
Kmt2d -/- line 1, D14, exp2 |
| GSM8171494 |
Kmt2d -/- line 2, D14, exp2 |
| GSM8171495 |
Kdm6a +/+ line 2, D14, exp2 |
| GSM8171496 |
Kdm6a +/+ line 3, D14, exp2 |
| GSM8171497 |
Kdm6a +/+ line 4, D14, exp2 |
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| Relations |
| BioProject |
PRJNA1092249 |
| Supplementary file |
Size |
Download |
File type/resource |
| GSE262539_RAW.tar |
102.9 Mb |
(http)(custom) |
TAR (of SF) |
SRA Run Selector |
| Raw data are available in SRA |
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