#nlmff — Public Fediverse posts
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New preprint: "Stoichiometric transcription factor partnerships control GABAergic neuron fate allocation."
Cell identity in development is often described as a combinatorial transcription factor "code." We find it is also quantitative: not only which factors are present, but their relative abundance, can shape a cell's fate.
In the developing basal ganglia, a pool of undifferentiated progenitors gives rise to several GABAergic neuron types, including D1 and D2 medium spiny neurons. Using our in vivo clonal perturbation sequencing and clone2vec, we find that losing SP9 shifts the clonal fate bias of progenitors from D2 neurons toward other GABAergic fates.
The readout uses two modes of genome binding: at GC-rich promoters SP9 binds DNA directly and activates; at distal enhancers it binds indirectly, tethered by DLX, acting as a combinatorial repressor with the NuRD complex. When DLX is in excess it sequesters SP9 away from its activating targets, so a graded shift in the SP9:DLX ratio becomes a discrete fate choice. An SP9 variant linked to neurodevelopmental disorders impairs the activator mode.
With thanks to the team, collaborators, and to #SFARI, the #DFG and the #NLMFF.
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Our research is now supported by a 2024 Simons Foundation Autism Research Initiative (SFARI) Pilot Award, co-funded by the Nancy Lurie Marks Family Foundation (NLMFF). I am grateful to both SFARI and NLMFF for investing in high-risk, high-reward science to advance understanding of autism spectrum disorders (ASD) and neurodevelopmental disorders.
The project will explore how mutations in chromatin regulators ASH1L and SETBP1 impair their crucial role in guiding the development of GABAergic neurons—key cells maintaining the brain’s balance between excitation and inhibition. Disruptions in this process are strongly linked to ASD, but the molecular pathways remain poorly understood.
By integrating genomic, proteomic, and functional approaches, we aim to reveal how these enzymes regulate gene activity during inhibitory neuron development and how their dysfunction contributes to ASD.
Official announcements:
SFARI: https://www.sfari.org/2025/04/08/announcing-the-recipients-of-the-2024-pilot-and-pilot-progression-awards/
NLMFF: https://www.nlmfoundation.org/grant/epigenetic-regulators-ash1l-and-setbp1-in-gabaergic-neuron-development-and-asd/#newsmayerlab #SFARI #NLMFF #AutismResearch #Neurodevelopment #Epigenetics #GABA #Genomics #Chromatin #Neuroscience