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MECP2-related pathways are dysregulated in a cortical organoid model of myotonic dystrophy.

Kathryn H Morelli, Wenhao Jin, Shashank Shathe, Assael A Madrigal, Krysten L Jones, Joshua L Schwartz, Tristan Bridges, Jasmine R Mueller, Archana Shankar, Isaac A Chaim, John W Day, Gene W Yeo

Science translational medicine · 2022 · Vol. 14 (651) · pp. eabn2375

PubMed ↗ DOI ↗ PMC full text ↗

Abstract

Myotonic dystrophy type 1 (DM1) is a multisystem, autosomal-dominant inherited disorder caused by CTG microsatellite repeat expansions (MREs) in the 3' untranslated region of the dystrophia myotonica-protein kinase (<i>DMPK</i>) gene. Despite its prominence as the most common adult-onset muscular dystrophy, patients with congenital to juvenile-onset forms of DM1 can present with debilitating neurocognitive symptoms along the autism spectrum, characteristic of possible in utero cortical defects. However, the molecular mechanism by which CTG MREs lead to these developmental central nervous system (CNS) manifestations is unknown. Here, we showed that CUG foci found early in the maturation of three-dimensional (3D) cortical organoids from DM1 patient-derived induced pluripotent stem cells (iPSCs) cause hyperphosphorylation of CUGBP Elav-like family member 2 (CELF2) protein. Integrative single-cell RNA sequencing and enhanced cross-linking and immunoprecipitation (eCLIP) analysis revealed that reduced CELF2 protein-RNA substrate interactions results in misregulation of genes critical for excitatory synaptic signaling in glutamatergic neurons, including key components of the methyl-CpG binding protein 2 (MECP2) pathway. Comparisons to MECP2<sup>(y/-)</sup> cortical organoids revealed convergent molecular and cellular defects such as glutamate toxicity and neuronal loss. Our findings provide evidence suggesting that early-onset DM1 might involve neurodevelopmental disorder-associated pathways and identify <i>N</i>-methyl-d-aspartic acid (NMDA) antagonists as potential treatment avenues for neuronal defects in DM1.

Linked datasets 4

GSE201898 GSE · via ncbi_elink
GEO ↗

MECP2-related pathways are dysregulated in a cortical organoid model of Myotonic dystrophy

Homo sapiens

GSE201897 GSE · via ncbi_elink
GEO ↗

MECP2-related pathways are dysregulated in a cortical organoid model of Myotonic dystrophy [bulk RNA-Seq]

Homo sapiens

64 data files
FileTypeSize
CVB_0m_rep1_R1.fastq.gz RNA-Seq 2.2 GB
CVB_0m_rep2_R1.fastq.gz RNA-Seq 13.0 GB
CVB_2m_rep1_R1.fastq.gz RNA-Seq 1.5 GB
CVB_2m_rep2_R1.fastq.gz RNA-Seq 4.2 GB
CVB_4m_rep1_R1.fastq.gz RNA-Seq 13.6 GB
CVB_4m_rep2_R1.fastq.gz RNA-Seq 12.1 GB
CVB_8m_rep1_R1.fastq.gz RNA-Seq 3.8 GB
CVB_8m_rep2_R1.fastq.gz RNA-Seq 5.6 GB
DM1200_0m_rep1_R1.fastq.gz RNA-Seq 4.4 GB
DM1200_0m_rep2_R1.fastq.gz RNA-Seq 2.8 GB
DM1200_2m_rep1_R1.fastq.gz RNA-Seq 4.0 GB
DM1200_2m_rep2_R1.fastq.gz RNA-Seq 307.3 MB
DM1200_4m_rep1_R1.fastq.gz RNA-Seq 6.1 GB
DM1200_4m_rep2_R1.fastq.gz RNA-Seq 6.3 GB
DM1200_8m_rep1_R1.fastq.gz RNA-Seq 24.5 GB
DM1200_8m_rep2_R1.fastq.gz RNA-Seq 1.1 GB
DM600_0m_rep1_R1.fastq.gz RNA-Seq 51.2 KB
DM600_0m_rep2_R1.fastq.gz RNA-Seq 5.8 GB
DM600_2m_rep1_R1.fastq.gz RNA-Seq 10.0 GB
DM600_2m_rep2_R1.fastq.gz RNA-Seq 9.5 GB
DM600_4m_rep1_R1.fastq.gz RNA-Seq 4.7 GB
DM600_4m_rep2_R1.fastq.gz RNA-Seq 12.3 GB
DM600_8m_rep1_R1.fastq.gz RNA-Seq 4.2 GB
DM600_8m_rep2_R1.fastq.gz RNA-Seq 6.0 GB
Kin_0m_rep1_R1.fastq.gz RNA-Seq 4.1 GB
Kin_0m_rep2_R1.fastq.gz RNA-Seq 4.5 GB
Kin_2m_rep1_R1.fastq.gz RNA-Seq 4.3 GB
Kin_2m_rep2_R1.fastq.gz RNA-Seq 4.1 GB
Kin_4m_rep1_R1.fastq.gz RNA-Seq 8.0 GB
Kin_4m_rep2_R1.fastq.gz RNA-Seq 6.7 GB
Kin_8m_rep1_R1.fastq.gz RNA-Seq 5.2 GB
Kin_8m_rep2_R1.fastq.gz RNA-Seq 6.4 GB
SRR18976210_GSM6077745 RNA-Seq 6.4 GB
SRR18976211_GSM6077744 RNA-Seq 5.2 GB
SRR18976212_GSM6077743 RNA-Seq 6.7 GB
SRR18976213_GSM6077742 RNA-Seq 8.0 GB
SRR18976214_GSM6077741 RNA-Seq 4.1 GB
SRR18976215_GSM6077740 RNA-Seq 4.3 GB
SRR18976216_GSM6077739 RNA-Seq 4.5 GB
SRR18976217_GSM6077738 RNA-Seq 4.1 GB
SRR18976218_GSM6077737 RNA-Seq 6.0 GB
SRR18976219_GSM6077736 RNA-Seq 4.2 GB
SRR18976220_GSM6077735 RNA-Seq 12.3 GB
SRR18976221_GSM6077734 RNA-Seq 4.7 GB
SRR18976222_GSM6077733 RNA-Seq 9.5 GB
SRR18976223_GSM6077732 RNA-Seq 10.0 GB
SRR18976224_GSM6077731 RNA-Seq 5.8 GB
SRR18976225_GSM6077730 RNA-Seq
SRR18976226_GSM6077729 RNA-Seq 1.1 GB
SRR18976227_GSM6077728 RNA-Seq 24.5 GB
SRR18976228_GSM6077727 RNA-Seq 6.3 GB
SRR18976229_GSM6077726 RNA-Seq 6.1 GB
SRR18976230_GSM6077725 RNA-Seq 307.0 MB
SRR18976231_GSM6077724 RNA-Seq 4.0 GB
SRR18976232_GSM6077723 RNA-Seq 2.8 GB
SRR18976233_GSM6077722 RNA-Seq 4.4 GB
SRR18976234_GSM6077721 RNA-Seq 5.6 GB
SRR18976235_GSM6077720 RNA-Seq 3.8 GB
SRR18976236_GSM6077719 RNA-Seq 12.1 GB
SRR18976237_GSM6077718 RNA-Seq 13.6 GB
SRR18976238_GSM6077717 RNA-Seq 4.2 GB
SRR18976239_GSM6077716 RNA-Seq 1.5 GB
SRR18976240_GSM6077715 RNA-Seq 13.0 GB
SRR18976241_GSM6077714 RNA-Seq 2.2 GB
GSE201891 GSE · via ncbi_elink
GEO ↗

MECP2-related pathways are dysregulated in a cortical organoid model of Myotonic dystrophy [scRNA-Seq]

Homo sapiens

11 data files
FileTypeSize
Control_6M_possorted_genome_bam.bam RNA-Seq 15.2 GB
DM1200_6M_possorted_genome_bam.bam RNA-Seq 13.0 GB
DM600_6M_possorted_genome_bam.bam RNA-Seq 13.2 GB
MECP2_KO_possorted_genome_bam.bam RNA-Seq 6.8 GB
MECP2_WT_possorted_genome_bam.bam RNA-Seq 9.3 GB
SRR18972861_GSM6077648 RNA-Seq 9.3 GB
SRR18972861.lite RNA-Seq 9.3 GB
SRR18972862_GSM6077647 RNA-Seq 6.8 GB
SRR18972863_GSM6077646 RNA-Seq 13.2 GB
SRR18972864_GSM6077645 RNA-Seq 13.0 GB
SRR18972865_GSM6077644 RNA-Seq 15.2 GB
GSE201895 GSE · via ncbi_elink
GEO ↗

MECP2-related pathways are dysregulated in a cortical organoid model of Myotonic dystrophy [eCLIP]

Homo sapiens

32 data files
FileTypeSize
Control1_6m_rep1_INPUT.fastq.gz OTHER 2.1 GB
Control1_6m_rep1_IP.fastq.gz OTHER 438.8 MB
Control1_6m_rep2_INPUT.fastq.gz OTHER 799.4 MB
Control1_6m_rep2_IP.fastq.gz OTHER 335.5 MB
Control2_6m_rep1_INPUT.fastq.gz OTHER 1.4 GB
Control2_6m_rep1_IP.fastq.gz OTHER 3.8 GB
Control2_6m_rep2_INPUT.fastq.gz OTHER 167.8 MB
Control2_6m_rep2_IP.fastq.gz OTHER 167.1 MB
DM1200_6m_rep1_INPUT.fastq.gz OTHER 155.0 MB
DM1200_6m_rep1_IP.fastq.gz OTHER 285.0 MB
DM1200_6m_rep2_INPUT.fastq.gz OTHER 866.8 MB
DM1200_6m_rep2_IP.fastq.gz OTHER 1.6 GB
DM600_6m_rep1_INPUT.fastq.gz OTHER 773.5 MB
DM600_6m_rep1_IP.fastq.gz OTHER 1.2 GB
DM600_6m_rep2_INPUT.fastq.gz OTHER 505.2 MB
DM600_6m_rep2_IP.fastq.gz OTHER 815.8 MB
SRR18973017_GSM6077706 OTHER 505.0 MB
SRR18973018_GSM6077704 OTHER 773.0 MB
SRR18973019_GSM6077702 OTHER 866.0 MB
SRR18973020_GSM6077703 OTHER 1.6 GB
SRR18973021_GSM6077705 OTHER 1.2 GB
SRR18973022_GSM6077707 OTHER 815.0 MB
SRR18973023_GSM6077701 OTHER 285.0 MB
SRR18973024_GSM6077699 OTHER 167.0 MB
SRR18973025_GSM6077697 OTHER 3.8 GB
SRR18973026_GSM6077695 OTHER 335.0 MB
SRR18973027_GSM6077694 OTHER 799.0 MB
SRR18973028_GSM6077696 OTHER 1.4 GB
SRR18973029_GSM6077698 OTHER 167.0 MB
SRR18973030_GSM6077700 OTHER 155.0 MB
SRR18973031_GSM6077693 OTHER 438.0 MB
SRR18973032_GSM6077692 OTHER 2.1 GB

Potentially related datasets 1

These accessions were text-mined from the PMC full text. They may be referenced for comparison, cited from other studies, or otherwise mentioned without being primary data for this paper.

Accession Source Title
GSE201898 GSE · GEO GEO ↗ MECP2-related pathways are dysregulated in a cortical organoid model of Myotonic dystrophy

Analysis pipelines 4

Pipeline Assay Steps Dataset
GSE201891 scRNA-seq Data Processing geo_data_processing scRNA-seq 3 GSE201891
GSE201895 eCLIP Data Processing geo_data_processing eCLIP 8 GSE201895
GSE201897 RNA-seq Data Processing geo_data_processing RNA-seq 3 GSE201897
GSE201898 Data Processing geo_data_processing — 3 GSE201898
Funding 12 grants
Grant Funder
U24 HG009889 NHGRI NIH HHS (United States)
S10 OD026929 NIH HHS (United States)
R01 HG004659 NHGRI NIH HHS (United States)
R01 NS103172 NINDS NIH HHS (United States)
U41 HG009889 NHGRI NIH HHS (United States)
P01 AI132122 NIAID NIH HHS (United States)
S10 OD025052 NIH HHS (United States)
U19 MH107367 NIMH NIH HHS (United States)
R01 AI123202 NIAID NIH HHS (United States)
K12 GM068524 NIGMS NIH HHS (United States)
F32 NS112654 NINDS NIH HHS (United States)
R01 EY029166 NEI NIH HHS (United States)