ASCL1 interacts with the mSWI/SNF at distal regulatory elements to regulate neural differentiation

Paun, O.; Tan, Y. X.; Patel, H.; Strohbuecker, S.; Ghanate, A.; Cobolli Gigli, C.; Sopena, M. L.; Gerontogianni, L.; Goldstone, R.; Ang, S.-L.; Guillemot, F.; Dias, C.

doi:10.1101/2022.10.09.510609

bioRxiv · 10.1101/2022.10.09.510609

ASCL1 interacts with the mSWI/SNF at distal regulatory elements to regulate neural differentiation

Paun, O.·Tan, Y. X.·Patel, H.·Strohbuecker, S.·Ghanate, A.·Cobolli Gigli, C.·Sopena, M. L.·Gerontogianni, L.·Goldstone, R.·Ang, S.-L.·Guillemot, F.·Dias, C.

View original source ↗Export metadata ↓

Abstract

AO_SCPLOWBSTRACTC_SCPLOWPioneer transcription factors are thought to play pivotal roles in developmental processes by binding nucleosomal DNA to activate gene expression. The role of neurogenic pioneer factor ASCL1 in shaping chromatin landscape in human neurogenesis remains unclear. Here we show that ASCL1 acts as a pioneer transcription factor in a transient population of progenitors. Using an in vitro ASCL1 knockout model we show it drives progenitor differentiation by cis-regulation both as a classical pioneer factor and as a non-pioneer remodeler, where ASCL1 binds permissive chromatin to induce chromatin conformation changes. We find ASCL1 directly interacts with mammalian BAF SWI/SNF chromatin remodeling complexes, essential for neurogenesis and involved in multiple neurodevelopmental disorders. ASCL1 acts as a non-pioneer chromatin remodeler to regulate gene expression at a subset of loci, requiring mBAF SWI/SNFs ATPase activity for cis-regulation of gene expression. Our findings demonstrate that ASCL1 is a key chromatin remodeler in human neurogenesis, uncovering an alternative mechanism of remodeling function dependent on partner ATPase activity.

Explore related subjects

developmental biology Preprint

Keep this discovery

Explore connections, maps & timelines

BibTeX RIS

Paun, O., Tan, Y. X., Patel, H., Strohbuecker, S., Ghanate, A., Cobolli Gigli, C., Sopena, M. L., Gerontogianni, L., Goldstone, R., Ang, S.-L., Guillemot, F., Dias, C.. 2022-10-09. ASCL1 interacts with the mSWI/SNF at distal regulatory elements to regulate neural differentiation. https://doi.org/10.1101/2022.10.09.510609

Cite the original work for its findings. Save a collection to share your selection of sources.

KEEP EXPLORING

Related preprints

bioRxiv2026

Prenatal THC exposure alters metabolic gene expression and KEAP1 regulation in the mouse placental labyrinth

Introduction: Prenatal cannabinoid exposure may influence fetal development through changes in placental biology, yet its effects on metabolic gene regulation remain poorly understood. We examined the effects of {Delta}9-tetrahydrocannabinol (THC) and cannabidiol (CBD) on the mouse placental labyrinth zone. Methods: Pregnant C57BL/6JRj mice received THC (5 mg/kg), CBD (5 mg/kg), or vehicle daily by intraperitoneal injection from gestational day 5 to 17.5. Targeted NanoString profiling and pathway analysis were combined with RT-qPCR and protein measurements. Results: THC exposure reduced glutaminase (Gls), Kelch-like ECH-associated protein 1 (Keap1), and FMS-like tyrosine kinase 3 (Flt3) expression (false discovery rate = 0.0904 for each). Pathway analysis identified transcriptional changes in the nine-gene arginine-metabolism set (false discovery rate = 0.0527). No genes or pathways met the significance criteria following CBD exposure. RT-qPCR confirmed lower Keap1 expression with sexes pooled and identified lower Gls and Flt3 expression in male samples. KEAP1 protein abundance increased despite lower Keap1 mRNA, while nuclear factor erythroid 2-related factor 2 localization and heme oxygenase 1 (Hmox1) expression showed no significant differences. Discussion: These findings identify amino acid metabolic gene expression and KEAP1 regulation as complementary components of the placental response to prenatal THC exposure, connecting transcriptional changes with protein regulation within the placental exchange region.

developmental biology↗

bioRxiv2026

Mutually Repressive Transcription Factors Drive Intestinal Maturation for Weaning

In mammals, rapid neonatal growth depends on specialized intestinal enterocytes that absorb nutrients from milk. These cells exhibit distinct functions, morphologies, and gene expression programs that support neonatal nutrition before transitioning to an adult state at weaning. However, the transcriptional mechanisms that establish neonatal enterocyte identity and coordinate their maturation remain poorly understood. Here we show that the transcription factors BLIMP1 and CASZ1 form a central switch in the timing of enterocyte maturation. While BLIMP1 marks and promotes neonatal enterocytes, CASZ1 is expressed in adult enterocytes and is required for the proper timing of their emergence. Genetic analysis indicates that these neonatal and adult factors are mutually repressive, forming a genetic switch underlying weaning. This regulatory mechanism also controls glucocorticoid-induced maturation, a process relevant to both normal weaning and the clinical use of corticosteroids to promote epithelial maturation in preterm infants. We show that corticosteroids act directly on the intestinal epithelium and require CASZ1 to induce maturation. Together, these findings reveal a transcriptional mechanism that coordinates intestinal epithelial identity with the changing nutritional demands of early life and mediates the response to maturation-promoting hormones.

developmental biology↗

bioRxiv2026

Functional Data Clustering of Filopodia Dynamics

Notch signaling plays a significant role in tissue patterning. During patterning of the fruit fly dorsal thorax peripheral nervous system, basal filopodia extend the spatial range of cell-cell communication, yet it is still unclear how Notch is activated in long range signaling via filopodia interaction. Filopodia undergo dynamic length changes during their lifetime, which could supply the mechanical pulling force required for notch activation. However, their dynamics are often characterized using individual scalar values such as maximum length and extension rate which could obscure more intricate dynamics. Our hypothesis is that signaling filopodia exhibit distinct and recurrent temporal patterns which can be identified by a consideration of their complete lifetime trajectories. Our work analyzes 60 filopodia trajectories at the basal surface of the fly dorsal thorax during patterning. Length profiles were smoothed using cubic B-splines and clustered by first reducing them to their dominant functional principal component followed by the application of various clustering algorithms. We found that 94.29% of the overall trajectory variation is explained by the first four functional principal components which account for variations in maximal length, extension and retraction rate, duration of stationary phase and length fluctuation frequency. Five recurrent temporal profiles (dynamic extension modes) with varying trajectory shapes and physical attributes, were identified using trimmed K-means. These findings demonstrate that whereas the major source of structural variation in filopodia profiles remains the length, extension rate and retraction rate, nontrivial combinations of these create distinct dynamic modes of extension which provide new insight into their length profiles. Our work thus offers a quantitative framework for future research connecting filopodia dynamic extension modes to productive Notch activation.

developmental biology↗