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Autism-associated chromatin remodeler CHD8 regulates erythroblast cytokinesis and fine-tunes the balance of Rho GTPase signaling
- Source :
- Cell reports, vol 40, iss 2
- Publication Year :
- 2022
-
Abstract
- CHD8 is an ATP-dependent chromatin-remodeling factor whose monoallelic mutation defines a subtype of autism spectrum disorders (ASDs). Previous work found that CHD8 is required for the maintenance of hematopoiesis by integrating ATM-P53-mediated survival of hematopoietic stem/progenitor cells (HSPCs). Here, by using Chd8F/FMx1-Cre combined with a Trp53F/F mouse model that suppresses apoptosis of Chd8-/- HSPCs, we identify CHD8 as an essential regulator of erythroid differentiation. Chd8-/-P53-/- mice exhibited severe anemia conforming to congenital dyserythropoietic anemia (CDA) phenotypes. Loss of CHD8 leads to drastically decreased numbers of orthochromatic erythroblasts and increased binucleated and multinucleated basophilic erythroblasts with a cytokinesis failure in erythroblasts. CHD8 binds directly to the gene bodies of multiple Rho GTPase signaling genes in erythroblasts, and loss of CHD8 results in their dysregulated expression, leading to decreased RhoA and increased Rac1 and Cdc42 activities. Our study shows that autism-associated CHD8 is essential for erythroblast cytokinesis.
- Subjects :
- rho GTP-Binding Proteins
Erythroblasts
Autism
Intellectual and Developmental Disabilities (IDD)
1.1 Normal biological development and functioning
Medical Physiology
cytokinesis
Regenerative Medicine
General Biochemistry, Genetics and Molecular Biology
Mice
CHD8
Underpinning research
Genetics
Animals
Autistic Disorder
Cytokinesis
erythroid differentiation
P53
Rho GTPases signaling
Hematology
Stem Cell Research
Chromatin
Brain Disorders
DNA-Binding Proteins
Mental Health
Immunology [CP]
Stem Cell Research - Nonembryonic - Non-Human
Biochemistry and Cell Biology
Tumor Suppressor Protein p53
Subjects
Details
- ISSN :
- 22111247
- Volume :
- 40
- Issue :
- 2
- Database :
- OpenAIRE
- Journal :
- Cell reports
- Accession number :
- edsair.doi.dedup.....2cc0772c62a929ce1cc890c1b268a7fe