Molecular dissection of the ChAHP complex subunits Adnp and Chd4 reveals common and divergent functions in retinal development
- 1Ottawa Hospital Research Institute
Abstract
Epigenetic remodelling is thought to regulate the progression of competence states in neural progenitor cells. Here, we examined the functions of the ChAHP chromatin remodelling complex during retinal development. ChAHP consists of the ATP-dependent nucleosome remodeller CHD4, the zinc finger and homeodomain transcription factor ADNP, and the HP1 heterochromatin proteins (Cbx1/3/5). Notably, both CHD4 and ADNP are genetically associated with neurodevelopmental disorders (NDDs), but ChAHP functions in neural development are not fully understood. In the retina, we found that both ADNP and CHD4 proteins were co-expressed ubiquitously in each cell type throughout development, and the two proteins formed a complex in vivo. Next, we generated retina-specific conditional knockouts (cKOs) to both Adnp and Chd4 using the Chx10-Cre driver. We observed phenotypic correspondence and divergence. Developmentally, we observed elevated cell death in both Adnp and Chd4 cKOs, but Adnp cKOs also exhibited deficits in progenitor numbers and proliferation. As a result, mature Adnp cKOs were hypoplastic with reductions in each cell type. We previously described a more complex phenotype in Chd4 cKOs, where cell fates were imbalanced and progenitor proliferation was prolonged, but these features were absent from the Adnp cKO. To understand how ChAHP regulates gene expression, we compared Adnp and Chd4 cKOs via scRNA-seq, which revealed common transcriptional signatures. However, Chd4 cKOs exhibited more severe effects on gene expression in line with its stronger effects on cell fate. We then performed cut&run-seq, which suggested that Adnp and Chd4 are recruited to the same genomic loci - many of which are also occupied by the Ctcf transcription factor. Taken together, our data suggest that ChAHP regulates retinal growth, but that CHD4 has additional ChAHP-independent functions in regulating progenitor fate decisions. These findings point to the idea that during neurogenesis, some brain regions may have greater dependence on ChAHP, and therefore greater vulnerability to genetic mutation.
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BibTeX
@misc{medisetti2026molecular,
title = {{Molecular dissection of the ChAHP complex subunits Adnp and Chd4 reveals common and divergent functions in retinal development}},
author = {S. Medisetti and A. Kalinina and S. Shah and M. A. Fayaz and S. Clemot-Dupont and D. J. Picketts and P. Mattar},
howpublished = {bioRxiv},
year = {2026},
month = oct,
doi = {10.64898/2026.10.29.762969},
url = {https://www.biorxiv.org/content/10.64898/2026.10.29.762969v1},
note = {CC BY-NC-ND},
}
RIS
TY - UNPB
TI - Molecular dissection of the ChAHP complex subunits Adnp and Chd4 reveals common and divergent functions in retinal development
AU - S. Medisetti
AU - A. Kalinina
AU - S. Shah
AU - M. A. Fayaz
AU - S. Clemot-Dupont
AU - D. J. Picketts
AU - P. Mattar
PY - 2026
DA - 2026/10/29
PB - bioRxiv
DO - 10.64898/2026.10.29.762969
UR - https://www.biorxiv.org/content/10.64898/2026.10.29.762969v1
AB - Epigenetic remodelling is thought to regulate the progression of competence states in neural progenitor cells. Here, we examined the functions of the ChAHP chromatin remodelling complex during retinal development. ChAHP consists of the ATP-dependent nucleosome remodeller CHD4, the zinc finger and homeodomain transcription factor ADNP, and the HP1 heterochromatin proteins (Cbx1/3/5). Notably, both CHD4 and ADNP are genetically associated with neurodevelopmental disorders (NDDs), but ChAHP functions in neural development are not fully understood. In the retina, we found that both ADNP and CHD4 proteins were co-expressed ubiquitously in each cell type throughout development, and the two proteins formed a complex in vivo. Next, we generated retina-specific conditional knockouts (cKOs) to both Adnp and Chd4 using the Chx10-Cre driver. We observed phenotypic correspondence and divergence. Developmentally, we observed elevated cell death in both Adnp and Chd4 cKOs, but Adnp cKOs also exhibited deficits in progenitor numbers and proliferation. As a result, mature Adnp cKOs were hypoplastic with reductions in each cell type. We previously described a more complex phenotype in Chd4 cKOs, where cell fates were imbalanced and progenitor proliferation was prolonged, but these features were absent from the Adnp cKO. To understand how ChAHP regulates gene expression, we compared Adnp and Chd4 cKOs via scRNA-seq, which revealed common transcriptional signatures. However, Chd4 cKOs exhibited more severe effects on gene expression in line with its stronger effects on cell fate. We then performed cut&run-seq, which suggested that Adnp and Chd4 are recruited to the same genomic loci - many of which are also occupied by the Ctcf transcription factor. Taken together, our data suggest that ChAHP regulates retinal growth, but that CHD4 has additional ChAHP-independent functions in regulating progenitor fate decisions. These findings point to the idea that during neurogenesis, some brain regions may have greater dependence on ChAHP, and therefore greater vulnerability to genetic mutation.
ER -