← Back to search

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.

Publication Types

["Journal Article", "Research Support, N.I.H., Extramural", "Research Support, Non-U.S. Gov't"]

Keywords

[]

MeSH Terms

["Adult", "CELF Proteins", "Humans", "Methyl-CpG-Binding Protein 2", "Myotonic Dystrophy", "Nerve Tissue Proteins", "Organoids", "RNA Splicing", "RNA-Binding Proteins", "Trinucleotide Repeat Expansion"]

Funding

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)

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_rep1_R1.fastq.gz RNA-Seq 2.2 GB
CVB_0m_rep2_R1.fastq.gz RNA-Seq 13.0 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_rep1_R1.fastq.gz RNA-Seq 1.5 GB
CVB_2m_rep2_R1.fastq.gz RNA-Seq 4.2 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_rep1_R1.fastq.gz RNA-Seq 13.6 GB
CVB_4m_rep2_R1.fastq.gz RNA-Seq 12.1 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_rep1_R1.fastq.gz RNA-Seq 3.8 GB
CVB_8m_rep2_R1.fastq.gz RNA-Seq 5.6 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_rep1_R1.fastq.gz RNA-Seq 4.4 GB
DM1200_0m_rep2_R1.fastq.gz RNA-Seq 2.8 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_rep1_R1.fastq.gz RNA-Seq 4.0 GB
DM1200_2m_rep2_R1.fastq.gz RNA-Seq 307.3 MB
DM1200_2m_rep2_R1.fastq.gz RNA-Seq 307.3 MB
DM1200_4m_rep1_R1.fastq.gz RNA-Seq 6.1 GB
DM1200_4m_rep1_R1.fastq.gz RNA-Seq 6.1 GB
DM1200_4m_rep2_R1.fastq.gz RNA-Seq 6.3 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_rep1_R1.fastq.gz RNA-Seq 24.5 GB
DM1200_8m_rep2_R1.fastq.gz RNA-Seq 1.1 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_rep1_R1.fastq.gz RNA-Seq 51.2 KB
DM600_0m_rep2_R1.fastq.gz RNA-Seq 5.8 GB
DM600_0m_rep2_R1.fastq.gz RNA-Seq 5.8 GB
DM600_2m_rep1_R1.fastq.gz RNA-Seq 10.0 GB
DM600_2m_rep1_R1.fastq.gz RNA-Seq 10.0 GB
DM600_2m_rep2_R1.fastq.gz RNA-Seq 9.5 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_rep1_R1.fastq.gz RNA-Seq 4.7 GB
DM600_4m_rep2_R1.fastq.gz RNA-Seq 12.3 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_rep1_R1.fastq.gz RNA-Seq 4.2 GB
DM600_8m_rep2_R1.fastq.gz RNA-Seq 6.0 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_rep1_R1.fastq.gz RNA-Seq 4.1 GB
Kin_0m_rep2_R1.fastq.gz RNA-Seq 4.5 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_rep1_R1.fastq.gz RNA-Seq 4.3 GB
Kin_2m_rep2_R1.fastq.gz RNA-Seq 4.1 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_rep1_R1.fastq.gz RNA-Seq 8.0 GB
Kin_4m_rep2_R1.fastq.gz RNA-Seq 6.7 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_rep1_R1.fastq.gz RNA-Seq 5.2 GB
Kin_8m_rep2_R1.fastq.gz RNA-Seq 6.4 GB
Kin_8m_rep2_R1.fastq.gz RNA-Seq 6.4 GB
GSE201891 GSE via ncbi_elink
GEO

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

Homo sapiens
10 data files
FileTypeSize
Control_6M_possorted_genome_bam.bam RNA-Seq 15.2 GB
Control_6M_possorted_genome_bam.bam RNA-Seq 15.2 GB
DM1200_6M_possorted_genome_bam.bam RNA-Seq 13.0 GB
DM1200_6M_possorted_genome_bam.bam RNA-Seq 13.0 GB
DM600_6M_possorted_genome_bam.bam RNA-Seq 13.2 GB
DM600_6M_possorted_genome_bam.bam RNA-Seq 13.2 GB
MECP2_KO_possorted_genome_bam.bam RNA-Seq 6.8 GB
MECP2_KO_possorted_genome_bam.bam RNA-Seq 6.8 GB
MECP2_WT_possorted_genome_bam.bam RNA-Seq 9.3 GB
SRR18972861.lite RNA-Seq 9.3 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_INPUT.fastq.gz OTHER 2.1 GB
Control1_6m_rep1_IP.fastq.gz OTHER 438.8 MB
Control1_6m_rep1_IP.fastq.gz OTHER 438.8 MB
Control1_6m_rep2_INPUT.fastq.gz OTHER 799.4 MB
Control1_6m_rep2_INPUT.fastq.gz OTHER 799.4 MB
Control1_6m_rep2_IP.fastq.gz OTHER 335.5 MB
Control1_6m_rep2_IP.fastq.gz OTHER 335.5 MB
Control2_6m_rep1_INPUT.fastq.gz OTHER 1.4 GB
Control2_6m_rep1_INPUT.fastq.gz OTHER 1.4 GB
Control2_6m_rep1_IP.fastq.gz OTHER 3.8 GB
Control2_6m_rep1_IP.fastq.gz OTHER 3.8 GB
Control2_6m_rep2_INPUT.fastq.gz OTHER 167.8 MB
Control2_6m_rep2_INPUT.fastq.gz OTHER 167.8 MB
Control2_6m_rep2_IP.fastq.gz OTHER 167.1 MB
Control2_6m_rep2_IP.fastq.gz OTHER 167.1 MB
DM1200_6m_rep1_INPUT.fastq.gz OTHER 155.0 MB
DM1200_6m_rep1_INPUT.fastq.gz OTHER 155.0 MB
DM1200_6m_rep1_IP.fastq.gz OTHER 285.0 MB
DM1200_6m_rep1_IP.fastq.gz OTHER 285.0 MB
DM1200_6m_rep2_INPUT.fastq.gz OTHER 866.8 MB
DM1200_6m_rep2_INPUT.fastq.gz OTHER 866.8 MB
DM1200_6m_rep2_IP.fastq.gz OTHER 1.6 GB
DM1200_6m_rep2_IP.fastq.gz OTHER 1.6 GB
DM600_6m_rep1_INPUT.fastq.gz OTHER 773.5 MB
DM600_6m_rep1_INPUT.fastq.gz OTHER 773.5 MB
DM600_6m_rep1_IP.fastq.gz OTHER 1.2 GB
DM600_6m_rep1_IP.fastq.gz OTHER 1.2 GB
DM600_6m_rep2_INPUT.fastq.gz OTHER 505.2 MB
DM600_6m_rep2_INPUT.fastq.gz OTHER 505.2 MB
DM600_6m_rep2_IP.fastq.gz OTHER 815.8 MB
DM600_6m_rep2_IP.fastq.gz OTHER 815.8 MB

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.

GSE201898 GSE GEO
GEO

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

Analysis Pipelines (4)

GSE201891 scRNA-seq Data Processing 3 steps
scRNA-seq geo_data_processing GSE201891
GSE201895 eCLIP Data Processing 8 steps
eCLIP geo_data_processing GSE201895
GSE201897 RNA-seq Data Processing 3 steps
RNA-seq geo_data_processing GSE201897
GSE201898 Data Processing 3 steps
geo_data_processing GSE201898