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This study investigates how Trisomy 21 (Down syndrome) affects the development of neural progenitor cells into neurons using stem cell models. The researchers found that Trisomy 21 neural progenitor cells maintain repressive chromatin structures, particularly increased H3K27me3 histone marks, over genes important for neuronal development, preventing proper activation of neurogenic programs and leading to reduced neuron production and continued cell proliferation. Treatment with an inhibitor targeting the enzyme complex responsible for H3K27 methylation partially restored normal neurogenesis in Trisomy 21 cells.
Why it matters
These findings reveal a specific chromatin-based mechanism underlying neurodevelopmental defects in Down syndrome and suggest that epigenetic modifications could be potential therapeutic targets. The identification of PRC2 inhibitors as a way to partially restore neurogenesis provides a proof-of-concept for developing interventions to address cognitive impairments associated with Down syndrome.
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⚠️ Preprint – Noch nicht peer-reviewed
Dieser Artikel wurde noch nicht von unabhängigen Experten begutachtet. Die Ergebnisse sind vorläufig und sollten mit Vorsicht interpretiert werden.
Correct neural progenitor cell (NPC) fate specification is essential to produce the full complement of neurons and glia needed for proper brain structure and function. Neurodevelopmental disorders, including the autosomal aneuploidy Down syndrome (DS), or Trisomy 21 (T21), are frequently associated with impaired cell fate decisions which ultimately drive differences in overall brain size and cell type composition through unknown mechanisms. To uncover mechanisms driving altered NPC fate in T21, we leverage paired single-nuclei transcriptomic and epigenomic analyses of human induced pluripotent stem cell (iPSC)-derived NPCs and their differentiated progeny coupled with in depth clonal cell fate, cell cycle, and proteomic analyses. Here we show that T21 NPCs fail to activate an orchestrated neurogenic program during the earliest stages of fate specification, instead maintaining a repressive chromatin structure over neurogenic loci, leading to reduced neurogenesis and continued NPC proliferation. We identify novel enrichment of the repressive histone mark H3K27me3 at fate instructive genes dysregulated across diverse cell and tissue types in T21, with corresponding genome-wide changes in H3K27me3 binding in T21 NPCs. Moreover, pharmacological treatment with an inhibitor of the Polycomb repressive complex 2 (PRC2) which catalyzes H3K27 methylation, is sufficient to partially restore neurogenesis in T21 cells. Collectively, our analyses reveal a chromatin mechanism influencing neurogenic defects in T21.
Source: Aberrant chromatin remodeling influences human neural cell fate change in Trisomy 21